Deuterium-Modified Brigatinib Derivatives, Pharmaceutical Compositions Comprising Same, And Use Thereof

ABSTRACT

The present invention relates to the field of pharmaceutical chemistry, and relates to a deuterium-modified Brigatinib derivative, preparation method thereof, pharmaceutical composition containing the same and the uses of the deuterium-modified Brigatinib derivative and the pharmaceutical composition thereof in preparing a medicament for treating the disease mediated by anaplastic lymphoma kinase. The deuterium-modified Brigatinib derivative of the present invention has an excellent inhibitory activity on anaplastic lymphoma kinase and has better pharmacodynamic or pharmacokinetic properties relative to Brigatinib.

REFERENCE TO RELATED APPLICATION

The present application claims the benefit of Chinese invention patentapplication No. 201510846894.0 filed on Nov. 27, 2015 in the StateIntellectual Property Office of the P. R. China.

TECHNICAL FIELD

The present invention belongs to the field of pharmaceutical chemistry,and relates to a deuterium-modified Brigatinib derivative, a preparationmethod thereof, a pharmaceutical composition comprising thedeuterium-modified Brigatinib derivative and a use of thedeuterium-modified Brigatinib derivative and a pharmaceuticalcomposition thereof for the preparation of a treatment for diseasesmediated by anaplastic lymphoma kinases.

BACKGROUND

Brigatinib, with a chemical name of5-chloro-N⁴-[2-(dimethylphosphonyl)phenyl]-N²-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine,is an anaplastic lymphoma kinase (AKL) inhibitor developed by ARIADPharmaceuticals, Inc, which can also inhibit EGFR and c-ros oncogene 1(ROS1), and it thus can be used for treating ALK-positive non-small celllung cancer and is currently in Phase II clinical trials. In October2014, the US FDA granted its breakthrough therapeutic drugqualification. The results from Phase I/II clinical trials show thatBrigatinib has persistent anti-tumor activity in patients withALK-positive non-small cell lung cancer (including those with brainmetastases).

Poor properties of absorption, distribution, metabolism and/or excretion(ADME) have been known as main reasons for failure of clinical trials ofnumerous drug candidates. The application ranges of many drugs currentlyon the market have been also limited due to their poor ADME properties.Rapid metabolism of drugs will cause many drugs, which could havetreated diseases with high efficient, difficult to be prepared intomedicine, due to excessively rapid metabolism and clearance from thebody. Although the problem of the rapid clearance of drugs may be solvedby frequent or high-dose administration, such approaches may presentseveral problems, such as poor patient compliance, side effects causedby high-dose administration, increased therapy costs and the like.Furthermore, rapidly metabolized drugs may also expose patients toadverse toxicity or reactive metabolites.

Although Brigatinib as an inhibitor of ALK can effectively treatALK-positive non-small cell lung cancer, it is still challenging todevelop a novel compound which can treat ALK-positive non-small celllung cancer and has good oral bioavailability and druggability.Therefore, there still is a need for the development of a compoundsuitable as a therapeutic agent with selective inhibition activity foranaplastic lymphoma kinase (AKL) or having betterpharmacodynamics/pharmacokinetics in the art. The present inventionprovides such compounds.

SUMMARY OF THE INVENTION

The present invention provides a compound represented by Formula I, or apharmaceutically acceptable salt, solvate or prodrug thereof:

wherein

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are each independentlyselected from hydrogen (H) or deuterium (D),

provided that at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀and R₁₁ is selected from deuterium.

In an aspect, the present invention provides a compound represented byFormula I, or a pharmaceutically acceptable salt, solvate or prodrugthereof:

wherein

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are each independentlyselected from hydrogen (H) or deuterium (D);

provided that at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀and R₁₁ is selected from deuterium.

It will be appreciated that, when R₁ is selected from hydrogen ordeuterium, the corresponding structural unit (R₁)₃C— in the compound ofFormula I is —CH₃ or —CD₃; and when R₈ is selected from hydrogen ordeuterium, the corresponding structural unit —OC(R₈)₃ in the compound ofFormula I is —OCH₃ or —OCD₃.

It will be appreciated that, the two R₂ in the compound of formula I areidentical, that is, when one of them is hydrogen or deuterium, the otherone is correspondingly hydrogen or deuterium; the same understandingshould be applied to R₃, R₄, R₅, R₆ and R₇.

In some embodiments of the present invention, R₁ is selected fromdeuterium, and R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium.

In some embodiments of the present invention, R₁ is selected fromdeuterium, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium, and R₂ is identicalto R₃, R₄ is identical to R₅, R₆ is identical to R₇.

In some embodiments of the present invention, R₁ is selected fromdeuterium, R₈ is selected from hydrogen, and R₂, R₃, R₄, R₅, R₆, R₇, R₉,R₁₀ and R₁₁ are each independently selected from hydrogen or deuterium.

In some embodiments of the present invention, R₁ is selected fromdeuterium, R₈ is selected from hydrogen, R₂, R₃, R₄, R₅, R₆, R₇, R₉, R₁₀and R₁₁ are each independently selected from hydrogen or deuterium, andR₂ is identical to R₃, R₄ is identical to R₅, R₆ is identical to R₇.

In some embodiments of the present invention, R₁ is selected fromdeuterium, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen, and R₂, R₃,R₄, R₅, R₆ and R₇ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₁ is selected fromdeuterium, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen, R₂, R₃, R₄,R₅, R₆ and R₇ are each independently selected from hydrogen ordeuterium, and R₂ is identical to R₃, R₄ is identical to R₅, R₆ isidentical to R₇.

In some embodiments of the present invention, R₁ is selected fromdeuterium, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen, andR₂, R₃, R₄ and R₅ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₁ is selected fromdeuterium, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen, R₂,R₃, R₄ and R₅ are each independently selected from hydrogen ordeuterium, and R₂ is identical to R₃, R₄ is identical to R₅. In someembodiments of the present invention, R₁ is selected from deuterium, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen, and R₂ andR₃ are each independently selected from hydrogen or deuterium.

In some embodiments of the present invention, R₁ is selected fromdeuterium, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selected fromhydrogen, R₂ and R₃ are each independently selected from hydrogen ordeuterium, and R₂ is identical to R₃.

In some embodiments of the present invention, R₂ and R₃ are selectedfrom deuterium, and R₁, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium.

In some embodiments of the present invention, R₂ and R₃ are selectedfrom deuterium, R₁, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium, and R₄ is identicalto R₅, R₆ is identical to R₇.

In some embodiments of the present invention, R₂ and R₃ are selectedfrom deuterium, R₉, R₁₀ and R₁₁ are selected from hydrogen, and R₁, R₄,R₅, R₆, R₇ and R₈ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₂ and R₃ are selectedfrom deuterium, R₉, R₁₀ and R₁₁ are selected from hydrogen, R₁, R₄, R₅,R₆, R₇ and R₈ are each independently selected from hydrogen ordeuterium, and R₄ is identical to R₅, R₆ is identical to R₇.

In some embodiments of the present invention, R₂ and R₃ are selectedfrom deuterium, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen, and R₁,R₄, R₅, R₆ and R₇ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₂ and R₃ are selectedfrom deuterium, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen, R₁, R₄,R₅, R₆ and R₇ are each independently selected from hydrogen ordeuterium, and R₄ is identical to R₅, R₆ is identical to R₇.

In some embodiments of the present invention, R₂ and R₃ are selectedfrom deuterium, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen,and R₁, R₄ and R₅ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₂ and R₃ are selectedfrom deuterium, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen,R₁, R₄ and R₅ are each independently selected from hydrogen ordeuterium, and R₄ is identical to R₅.

In some embodiments of the present invention, R₂ and R₃ are selectedfrom deuterium, R₁ is selected from hydrogen, and R₄, R₅, R₆, R₇, R₈,R₉, R₁₀ and R₁₁ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₂ and R₃ are selectedfrom deuterium, R₁ is selected from hydrogen, R₄, R₅, R₆, R₇, R₈, R₉,R₁₀ and R₁₁ are each independently selected from hydrogen or deuterium,and R₄ is identical to R₅, R₆ is identical to R₇.

In some embodiments of the present invention, R₂ and R₃ are selectedfrom deuterium, R₁, R₉, R₁₀ and R₁₁ are selected from hydrogen, and R₄,R₅, R₆, R₇ and R₈ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₂ and R₃ are selectedfrom deuterium, R₁, R₉, R₁₀ and R₁₁ are selected from hydrogen, R₄, R₅,R₆, R₇ and R₈ are each independently selected from hydrogen ordeuterium, and R₄ is identical to R₅, R₆ is identical to R₇.

In some embodiments of the present invention, R₂ and R₃ are selectedfrom deuterium, R₁, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen, andR₄, R₅, R₆ and R₇ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₂ and R₃ are selectedfrom deuterium, R₁, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen, R₄,R₅, R₆ and R₇ are each independently selected from hydrogen ordeuterium, and R₄ is identical to R₅, R₆ is identical to R₇.

In some embodiments of the present invention, R₂ and R₃ are selectedfrom deuterium, R₁, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selected fromhydrogen, and R₄ and R₅ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₂ and R₃ are selectedfrom deuterium, R₁, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selected fromhydrogen, R₄ and R₅ are each independently selected from hydrogen ordeuterium, and R₄ is identical to R₅.

In some embodiments of the present invention, R₁, R₂ and R₃ are selectedfrom deuterium, and R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium.

In some embodiments of the present invention, R₁, R₂ and R₃ are selectedfrom deuterium, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium, and R₄ is identicalto R₅, R₆ is identical to R₇.

In some embodiments of the present invention, R₁, R₂ and R₃ are selectedfrom deuterium, R₈ is selected from hydrogen, and R₄, R₅, R₆, R₇, R₉,R₁₀ and R₁₁ are each independently selected from hydrogen or deuterium.

In some embodiments of the present invention, R₁, R₂ and R₃ are selectedfrom deuterium, R₈ is selected from hydrogen, R₄, R₅, R₆, R₇, R₉, R₁₀and R₁₁ are each independently selected from hydrogen or deuterium, andR₄ is identical to R₅, R₆ is identical to R₇.

In some embodiments of the present invention, R₁, R₂ and R₃ are selectedfrom deuterium, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen, and R₄,R₅, R₆ and R₇ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₁, R₂ and R₃ are selectedfrom deuterium, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen, R₄, R₅,R₆ and R₇ are each independently selected from hydrogen or deuterium,and R₄ is identical to R₅, R₆ is identical to R₇.

In some embodiments of the present invention, R₁, R₂ and R₃ are selectedfrom deuterium, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen,and R₄ and R₅ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₁, R₂ and R₃ are selectedfrom deuterium, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen,R₄ and R₅ are each independently selected from hydrogen or deuterium,and R₄ is identical to R₅. In some embodiments of the present invention,R₄ and R₅ are selected from deuterium, and R₁, R₂, R₃, R₆, R₇, R₈, R₉,R₁₀ and R₁₁ are each independently selected from hydrogen or deuterium.

In some embodiments of the present invention, R₄ and R₅ are selectedfrom deuterium, R₁, R₂, R₃, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium, and R₂ is identicalto R₃, R₆ is identical to R₇.

In some embodiments of the present invention, R₄ and R₅ are selectedfrom deuterium, R₉, R₁₀ and R₁₁ are selected from hydrogen, and R₁, R₂,R₃, R₆, R₇ and R₈ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₄ and R₅ are selectedfrom deuterium, R₉, R₁₀ and R₁₁ are selected from hydrogen, R₁, R₂, R₃,R₆, R₇ and R₈ are each independently selected from hydrogen ordeuterium, and R₂ is identical to R₃, R₆ is identical to R₇.

In some embodiments of the present invention, R₄ and R₅ are selectedfrom deuterium, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen, and R₁,R₂, R₃, R₆ and R₇ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₄ and R₅ are selectedfrom deuterium, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen, R₁, R₂,R₃, R₆ and R₇ are each independently selected from hydrogen ordeuterium, and R₂ is identical to R₃, R₆ is identical to R₇.

In some embodiments of the present invention, R₄ and R₅ are selectedfrom deuterium, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen,and R₁, R₂ and R₃ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₄ and R₅ are selectedfrom deuterium, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen,R₁, R₂ and R₃ are each independently selected from hydrogen ordeuterium, and R₂ is identical to R₃.

In some embodiments of the present invention, R₄ and R₅ are selectedfrom deuterium, R₁, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selected fromhydrogen, and R₂ and R₃ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₄ and R₅ are selectedfrom deuterium, R₁, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selected fromhydrogen, R₂ and R₃ are each independently selected from hydrogen ordeuterium, and R₂ is identical to R₃.

In some embodiments of the present invention, R₄ and R₅ are selectedfrom deuterium, R₁, R₂, R₃, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are eachselected from hydrogen or deuterium, and not all R₁, R₂, R₃, R₆, R₇, R₈,R₉, R₁₀ and R₁₁ are hydrogen.

In some embodiments of the present invention, R₄ and R₅ are selectedfrom deuterium, R₁, R₂, R₃, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium, not all R₁, R₂, R₃,R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are hydrogen, R₂ is identical to R₃, and R₆is identical to R₇.

In some embodiments of the present invention, R₂, R₃, R₄ and R₅ areselected from deuterium, and R₁, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium.

In some embodiments of the present invention, R₂, R₃, R₄ and R₅ areselected from deuterium, R₁, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium, and R₆ is identicalto R₇.

In some embodiments of the present invention, R₂, R₃, R₄ and R₅ areselected from deuterium, R₉, R₁₀ and R₁₁ are selected from hydrogen, andR₁, R₆, R₇ and R₈ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₂, R₃, R₄ and R₅ areselected from deuterium, R₉, R₁₀ and R₁₁ are selected from hydrogen, R₁,R₆, R₇ and R₈ are each independently selected from hydrogen ordeuterium, and R₆ is identical to R₇.

In some embodiments of the present invention, R₂, R₃, R₄ and R₅ areselected from deuterium, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen,and R₁, R₆ and R₇ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₂, R₃, R₄ and R₅ areselected from deuterium, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen,R₁, R₆ and R₇ are each independently selected from hydrogen ordeuterium, and R₆ is identical to R₇.

In some embodiments of the present invention, R₂, R₃, R₄ and R₅ areselected from deuterium, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selected fromhydrogen, and R₁ is selected from hydrogen or deuterium.

In some embodiments of the present invention, R₂, R₃, R₄ and R₅ areselected from deuterium, R₁ is selected from hydrogen, and R₆, R₇, R₈,R₉, R₁₀ and R₁₁ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₂, R₃, R₄ and R₅ areselected from deuterium, R₁ is selected from hydrogen, R₆, R₇, R₈, R₉,R₁₀ and R₁₁ are each independently selected from hydrogen or deuterium,and R₆ is identical to R₇.

In some embodiments of the present invention, R₂, R₃, R₄ and R₅ areselected from deuterium, R₁, R₉, R₁₀ and R₁₁ are selected from hydrogen,and R₆, R₇ and R₈ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₂, R₃, R₄ and R₅ areselected from deuterium, R₁, R₉, R₁₀ and R₁₁ are selected from hydrogen,R₆, R₇ and R₈ are each independently selected from hydrogen ordeuterium, and R₆ is identical to R₇.

In some embodiments of the present invention, R₁, R₂, R₃, R₄ and R₅ areselected from deuterium, and R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium.

In some embodiments of the present invention, R₁, R₂, R₃, R₄ and R₅ areselected from deuterium, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium, and R₆ is identicalto R₇.

In some embodiments of the present invention, R₁, R₂, R₃, R₄ and R₅ areselected from deuterium, R₉, R₁₀ and R₁₁ are selected from hydrogen, andR₆, R₇ and R₈ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₁, R₂, R₃, R₄ and R₅ areselected from deuterium, R₉, R₁₀ and R₁₁ are selected from hydrogen, R₆,R₇ and R₈ are each independently selected from hydrogen or deuterium,and R₆ is identical to R₇.

In some embodiments of the present invention, R₁, R₂, R₃, R₄ and R₅ areselected from deuterium, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen,and R₆ and R₇ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₁, R₂, R₃, R₄ and R₅ areselected from deuterium, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen,and R₆ and R₇ are each independently selected from hydrogen ordeuterium, and R₆ is identical to R₇.

In some embodiments of the present invention, R₆ and R₇ are selectedfrom deuterium, and R₁, R₂, R₃, R₄, R₅, R₈, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium.

In some embodiments of the present invention, R₆ and R₇ are selectedfrom deuterium, R₁, R₂, R₃, R₄, R₅, R₈, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium, and R₂ is identicalto R₃, R₄ is identical to R₅.

In some embodiments of the present invention, R₆ and R₇ are selectedfrom deuterium, R₉, R₁₀ and R₁₁ are selected from hydrogen, and R₁, R₂,R₃, R₄, R₅ and R₈ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₆ and R₇ are selectedfrom deuterium, R₉, R₁₀ and R₁₁ are selected from hydrogen, and R₁, R₂,R₃, R₄, R₅ and R₈ are each independently selected from hydrogen ordeuterium, and R₂ is identical to R₃, R₄ is identical to R₅.

In some embodiments of the present invention, R₆ and R₇ are selectedfrom deuterium, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen, and R₁,R₂, R₃, R₄ and R₅ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₆ and R₇ are selectedfrom deuterium, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen, R₁, R₂,R₃, R₄ and R₅ are each independently selected from hydrogen ordeuterium, and R₂ is identical to R₃, R₄ is identical to R₅.

In some embodiments of the present invention, R₆ and R₇ are selectedfrom deuterium, R₁, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen, andR₂, R₃, R₄ and R₅ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₆ and R₇ are selectedfrom deuterium, R₁, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen, R₂,R₃, R₄ and R₅ are each independently selected from hydrogen ordeuterium, and R₂ is identical to R₃, R₄ is identical to R₅.

In some embodiments of the present invention, R₆, R₇ and R₈ are selectedfrom deuterium, and R₁, R₂, R₃, R₄, R₅, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium.

In some embodiments of the present invention, R₆, R₇ and R₈ are selectedfrom deuterium, R₁, R₂, R₃, R₄, R₅, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium, and R₂ is identicalto R₃, R₄ is identical to R₅.

In some embodiments of the present invention, R₆, R₇ and R₈ are selectedfrom deuterium, R₁ is selected from hydrogen, and R₂, R₃, R₄, R₅, R₉,R₁₀ and R₁₁ are each independently selected from hydrogen or deuterium.

In some embodiments of the present invention, R₆, R₇ and R₈ are selectedfrom deuterium, R₁ is selected from hydrogen, R₂, R₃, R₄, R₅, R₉, R₁₀and R₁₁ are each independently selected from hydrogen or deuterium, andR₂ is identical to R₃, R₄ is identical to R₅.

In some embodiments of the present invention, R₆, R₇ and R₈ are selectedfrom deuterium, R₁, R₉, R₁₀ and R₁₁ are selected from hydrogen, and R₂,R₃, R₄ and R₅ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₆, R₇ and R₈ are selectedfrom deuterium, R₁, R₉, R₁₀ and R₁₁ are selected from hydrogen, R₂, R₃,R₄ and R₅ are each independently selected from hydrogen or deuterium,and R₂ is identical to R₃, R₄ is identical to R₅.

In some embodiments of the present invention, R₈ is selected fromdeuterium, and R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium.

In some embodiments of the present invention, R₈ is selected fromdeuterium, and R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium, and R₂ is identicalto R₃, R₄ is identical to R₅, R₆ is identical to R₇.

In some embodiments of the present invention, R₈ is selected fromdeuterium, R₆, R₇, R₉, R₁₀ and R₁₁ are selected from hydrogen, and R₁,R₂, R₃, R₄ and R₅ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₈ is selected fromdeuterium, R₆, R₇, R₉, R₁₀ and R₁₁ are selected from hydrogen, R₁, R₂,R₃, R₄ and R₅ are each independently selected from hydrogen ordeuterium, and R₂ is identical to R₃, R₄ is identical to R₅.

In some embodiments of the present invention, R₈ is selected fromdeuterium, R₁ is selected from hydrogen, and R₂, R₃, R₄, R₅, R₆, R₇, R₉,R₁₀ and R₁₁ are each independently selected from hydrogen or deuterium.

In some embodiments of the present invention, R₈ is selected fromdeuterium, R₁ is selected from hydrogen, and R₂, R₃, R₄, R₅, R₆, R₇, R₉,R₁₀ and R₁₁ are each independently selected from hydrogen or deuterium,and R₂ is identical to R₃, R₄ is identical to R₅, R₆ is identical to R₇.

In some embodiments of the present invention, R₈ is selected fromdeuterium, R₁, R₉, R₁₀ and R₁₁ are selected from hydrogen, and R₂, R₃,R₄, R₅, R₆ and R₇ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₈ is selected fromdeuterium, R₁, R₉, R₁₀ and R₁₁ are selected from hydrogen, R₂, R₃, R₄,R₅, R₆ and R₇ are each independently selected from hydrogen ordeuterium, and R₂ is identical to R₃, R₄ is identical to R₅, R₆ isidentical to R₇.

In some embodiments of the present invention, R₈ is selected fromdeuterium, R₁, R₆, R₇, R₉, R₁₀ and R₁₁ are selected from hydrogen, andR₂, R₃, R₄ and R₅ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₈ is selected fromdeuterium, R₁, R₆, R₇, R₉, R₁₀ and R₁₁ are selected from hydrogen, andR₂, R₃, R₄ and R₅ are each independently selected from hydrogen ordeuterium, and R₂ is identical to R₃, R₄ is identical to R₅. In someembodiments of the present invention, R₉ and R₁₀ are selected fromdeuterium, and R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₁₁ are eachindependently selected from hydrogen or deuterium.

In some embodiments of the present invention, R₉ and R₁₀ are selectedfrom deuterium, and R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₁₁ are eachindependently selected from hydrogen or deuterium, and R₂ is identicalto R₃, R₄ is identical to R₅, R₆ is identical to R₇.

In some embodiments of the present invention, R₁₁ is selected fromdeuterium, and R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀ are eachindependently selected from hydrogen or deuterium.

In some embodiments of the present invention, R₁₁ is selected fromdeuterium, and R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀ are eachindependently selected from hydrogen or deuterium, and R₂ is identicalto R₃, R₄ is identical to R₅, R₆ is identical to R₇.

In some embodiments of the present invention, R₁₀ and R₁₁ are selectedfrom deuterium, and R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are eachindependently selected from hydrogen or deuterium.

In some embodiments of the present invention, R₁₀ and R₁₁ are selectedfrom deuterium, and R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are eachindependently selected from hydrogen or deuterium, and R₂ is identicalto R₃, R₄ is identical to R₅, R₆ is identical to R₇.

In some embodiments of the present invention, R₁₀ and R₁₁ are selectedfrom deuterium, R₉ is selected from hydrogen, and R₁, R₂, R₃, R₄, R₅,R₆, R₇ and R₈ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₁₀ and R₁₁ are selectedfrom deuterium, R₉ is selected from hydrogen, R₁, R₂, R₃, R₄, R₅, R₆, R₇and R₈ are each independently selected from hydrogen or deuterium, andR₂ is identical to R₃, R₄ is identical to R₅, R₆ is identical to R₇.

In some embodiments of the present invention, R₉, R₁₀ and R₁₁ areselected from deuterium, and R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are eachindependently selected from hydrogen or deuterium.

In some embodiments of the present invention, R₉, R₁₀ and R₁₁ areselected from deuterium, and R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are eachindependently selected from hydrogen or deuterium, and R₂ is identicalto R₃, R₄ is identical to R₅, R₆ is identical to R₇.

In some embodiments of the present invention, R₁ and R₈ are selectedfrom deuterium, and R₂, R₃, R₄, R₅, R₆, R₇, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium.

In some embodiments of the present invention, R₁ and R₈ are selectedfrom deuterium, and R₂, R₃, R₄, R₅, R₆, R₇, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium, and R₂ is identicalto R₃, R₄ is identical to R₅, R₆ is identical to R₇.

In some embodiments of the present invention, R₁ and R₈ are selectedfrom deuterium, R₉, R₁₀ and R₁₁ are selected from hydrogen, and R₂, R₃,R₄, R₅, R₆ and R₇ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₁ and R₈ are selectedfrom deuterium, R₉, R₁₀ and R₁₁ are selected from hydrogen, and R₂, R₃,R₄, R₅, R₆ and R₇ are each independently selected from hydrogen ordeuterium, and R₂ is identical to R₃, R₄ is identical to R₅, R₆ isidentical to R₇.

In some embodiments of the present invention, R₁ and R₈ are selectedfrom deuterium, R₆, R₇, R₉, R₁₀ and R₁₁ are selected from hydrogen, andR₂, R₃, R₄ and R₅ are each independently selected from hydrogen ordeuterium.

In some embodiments of the present invention, R₁ and R₈ are selectedfrom deuterium, R₆, R₇, R₉, R₁₀ and R₁₁ are selected from hydrogen, andR₂, R₃, R₄ and R₅ are each independently selected from hydrogen ordeuterium, and R₂ is identical to R₃, R₄ is identical to R₅.

In some embodiments of the present invention, R₁, R₂, R₃, R₄, R₅, R₆, R₇and R₈ are each independently selected from hydrogen or deuterium, andR₉, R₁₀ and R₁₁ are each independently selected from hydrogen, providedthat at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ is selected fromdeuterium.

In some embodiments of the present invention, R₁, R₂, R₃, R₄, R₅, R₆, R₇and R₈ are each independently selected from hydrogen or deuterium, andR₉, R₁₀ and R₁₁ are each independently selected from hydrogen, providedthat at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ is selected fromdeuterium, and R₂ is identical to R₃, R₄ is identical to R₅, R₆ isidentical to R₇.

In some embodiments of the present invention, R₁, R₂, R₃, R₄, R₅, R₆,R₇, R₈, R₉, R₁₀ and R₁₁ are each independently selected from hydrogen ordeuterium, provided that at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈,R₉, R₁₀ and R₁₁ is selected from deuterium, and when R₄ and R₅ areselected from deuterium, not all R₁, R₂, R₃, R₆, R₇, R₈, R₉, R₁₀ and R₁₁are hydrogen.

In some embodiments of the present invention, R₁, R₂, R₃, R₄, R₅, R₆,R₇, R₈, R₉, R₁₀ and R₁₁ are each independently selected from hydrogen ordeuterium, provided that at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈,R₉, R₁₀ and R₁₁ is selected from deuterium, and when R₄ and R₅ areselected from deuterium, not all R₁, R₂, R₃, R₆, R₇, R₈, R₉, R₁₀ and R₁₁are hydrogen, and R₂ is identical to R₃, R₄ is identical to R₅, R₆ isidentical to R₇.

In some embodiments of the present invention, R₁, R₂, R₃, R₄, R₅, R₆,R₇, R₈, R₉, R₁₀ and R₁₁ are each independently selected from hydrogen ordeuterium, provided that at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈,R₉, R₁₀ and R₁₁ is selected from deuterium, and when R₁ and R₈ areselected from deuterium, not all R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀and R₁₁ are hydrogen.

In some embodiments of the present invention, R₁, R₂, R₃, R₄, R₅, R₆,R₇, R₈, R₉, R₁₀ and R₁₁ are each independently selected from hydrogen ordeuterium, provided that at least one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈,R₉, R₁₀ and R₁₁ is selected from deuterium, and when R₁ and R₈ areselected from deuterium, not all R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀and R₁₁ are hydrogen, and R₂ is identical to R₃, R₄ is identical to R₅,R₆ is identical to R₇.

In some embodiments of the present invention, the examples of thecompound of Formula I are as follows:

Number R₁ R₂ R₃ R₄ R₅ R₆ R₇ R₈ R₉ R₁₀ R₁₁ I-1 H H H H H H H D H H H I-2D H H H H H H H H H H I-3 D H H H H H H D H H H I-4 H H H D D H H H H HH I-5 H H H H H D D H H H H I-6 H D D D D H H H H H H I-7 D D D H H H HH H H H I-8 D D D D D H H H H H H I-9 H D D H H H H H H H H I-10 H H H HH D D D H H H I-11 H H H H H H H D D D D I-12 H H H H H H H D H D D

In some particular embodiments of the present invention, the compoundrepresented by Formula I is selected from the compounds represented bythe following formulas:

In another aspect, the present invention provides a method for preparingthe compound represented by Formula I, including but not limited to thefollowing schemes:

As shown in Scheme 1, a compound of Formula II is reduced by catalytichydrogenation to give a compound of Formula III; and under the action ofan acid, the compound of Formula III is reacted with a compound ofFormula IV to give the compound of Formula I.

As shown in Scheme 2, compounds of Formulas V and VI take placesubstitution reaction in the presence of a base to give the compound ofFormula II. The compound of Formula VI is commercially available.

As shown in Scheme 3, compounds of Formulas VII and IVIII take placereductive amination reaction, to give the compound of Formula II.

As shown in Scheme 4, a compound of Formula V reacts with a compound ofFormula IX in the presence of a base, to give the compound of FormulaVII, wherein the compound of Formula IX is commercially available.

As shown in Scheme 5, 5-fluoro-2-nitrophenol reacts with C(R₈)₃1 in thepresence of a base, to give the compound of Formula V, wherein5-fluoro-2-nitrophenol is commercially available.

As shown in Scheme 6, a compound of Formula X reacts with a compound ofFormula XI to give a compound of Formula XII, and the compound ofFormula XII is debenzylated by catalytic hydrogenation of Pd—C to givethe compound of Formula VIII. Among them, the compound of Formula X isprepared as the method in CN102675018A, and the compound of Formula XIis commercially available or is prepared as methods known in the art.

As shown in Scheme 7, 1-methylpiperazine reacts with sodium nitrite inhydrochloric acid to give a compound of Formula XIII, the compound ofFormula XIII is treated with heavy water in an alkaline condition togive a deuterated compound of Formula XIII-2, and then the compound ofFormula XIII-2 is catalytically reduced to give the compound of FormulaVIII-2, wherein 1-methylpiperazine is commercially available.

As shown in Scheme 8, deuterated piperazine hydrochloride (which can beprepared as the method in CN201510502945.8) reacts with di-t-butyldicarbonate in an alkaline condition to give a compound of Formula XIV,the compound of Formula XIV reacts with methyl p-toluenesulfonate underthe action of a base to give a compound of Formula XV, the compound ofFormula XV is subjected to de-protection under the action of an acid togive an acidic salt of the compound of Formula VIII-3, and then a freecompound of Formula VIII-3 is obtained under the action of a base.

As shown in Scheme 9, a compound of Formula XVI (which can be preparedas the method in CN201510502945.8) undergoes reductive aminationreaction in 37% formaldehyde solution and formic acid to give a compoundof Formula XVII, and the compound of Formula XVII is debenzylated bycatalytic hydrogenation with Pd—C to give the compound of FormulaVIII-4.

As shown in Scheme 10, the compound of Formula XVIII reacts with2,4,5-trichloropyrimidine in the presence of alkaline catalysis to givethe compound of Formula IV, wherein the compound of Formula XVIII iscommercially available.

Among them, deuterated methylating agents (such as deuteratediodomethane) can be commercially available, for example, purchased fromSigma-Aldrich; or can be prepared by known deuteration methods, forexample, it can be obtained by exchanging a non-deuterated compound inheavy water in the presence of acid catalyst.

The above Schemes show the synthetic methods constituting the presentinvention, which are used to describe applicable chemical methods byspecific examples, but not present the scope of the present invention ornot intended to limit. The chemical structures in the illustrationsherein depict variables that are defined, where appropriate, with thedefinition of the chemical groups at the corresponding positions in theformulas of the compounds herein, whether denoted with the same variablenames (i.e., R₁, R₂, R₃ and the like) or not. Appropriateness of achemical group in a chemical structural formula for synthesizing anothercompound is within the knowledge of those skilled in the art.

In the description of the preparation method according to the presentinvention, the definition of the groups R₁ to R₁₁ in the compounds isdescribed as above.

In another aspect, the present invention provides a pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundof Formula I or a pharmaceutically acceptable salt thereof, and one ormore pharmaceutically acceptable carriers or excipients.

The pharmaceutical composition of the present invention can be preparedby combining a compound of the present invention or the pharmaceuticallyacceptable salt thereof with suitable pharmaceutically acceptablecarriers. For example, it can be formulated into solid, semi-solid,liquid or gaseous preparations, such as tablets, pills, capsules,powders, granules, ointments, emulsions, suspensions, solutions,suppositories, injections, inhalants, gels, microspheres, aerosols andthe like.

Typical administration routes of compounds of the present invention orpharmaceutically acceptable salts, hydrates, solvates or prodrugsthereof, or pharmaceutical compositions thereof includes, but notlimited to, oral, rectal, transmucosal, intestinal administration, ortopical, transdermal, inhalation, parenteral, sublingual, intravaginal,intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous,and intravenous administration.

The pharmaceutical composition of the present invention may bemanufactured by methods well-known in the art, such as conventionalmixing method, dissolution method, granulation method, method forpreparing sugar-coated pills, grinding method, emulsification method,freeze-drying method and the like.

For oral administration, the pharmaceutical composition can beformulated by mixing an active compound with a pharmaceuticallyacceptable carrier well-known in the art. These carriers can allow thecompounds of the present invention to be formulated into tablets, pills,troches, dragees, capsules, liquids, gels, slurries, suspensions and thelike, for oral administration to patients.

A solid oral composition can be prepared by conventional mixing, fillingor tabletingmethod. For example, it can be obtained by the followingmethod: mixing the active compound with solid excipients, optionallymilling the resultant mixture, adding additional suitable adjuvants ifnecessary, and then processing the mixture into granules, to producetablet cores or dragee cores. Suitable adjuvants include, but notlimited to, adhesives, diluents, disintegrants, lubricants, glidants,sweeteners, flavoring agents or the like, such as, microcrystallinecellulose, glucose solution, arabic gum slurry, gelatin solution,sucrose and starch paste; talcum, starch, magnesium stearate, calciumstearate or stearic acid; lactose, sucrose, starch, mannitol, sorbitolor dicalcium phosphate; silicon dioxide; croscarmellose sodium,pregelatinized starch, sodium starch glycolate, alginic acid, cornstarch, potato starch, methylcellulose, agar, carboxymethyl cellulose,crosslinked polyvinylpyrrolidone and the like. The dragee core can beoptionally coated, especially with an enteric coating, according tomethods recognized in common drug practice.

The pharmaceutical composition can also be suitable for parenteraladministration, such as sterile solutions, suspensions or freeze-driedproducts in a suitable unit dosage form. An appropriate excipient suchas a bulking agent, a buffer agent, or surfactant can be used.

The compound represented by Formula I or the pharmaceutically acceptablesalt, solvate or prodrug thereof in the present invention can beadministered by any suitable routes and methods, for example orally orparenterally (e.g., intravenously). The therapeutically effective amountof the compound of Formula I ranges from about 0.0001 mg/Kg of bodyweight to 20 mg/Kg of body weight per day, for example from 0.001 mg/Kgof body weight to 10 mg/Kg of body weight per day.

The dose frequency of the compound of Formula I depends on needs ofindividual patients, for example, once or twice every day or more timesevery day. Administration can be intermittent, for example, where duringa period of several days, patients receives a daily dose of the compoundof Formula I, and during a period of next several or more days, they donot receive a daily dose of said compound.

In a further aspect, the present invention provides a method forinhibiting anaplastic lymphoma kinase (AKL), comprising administering atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising the compound of Formula I, topatients in need thereof.

In further another aspect, the present invention provides a method fortreating and/or preventing diseases mediated by anaplastic lymphomakinase (AKL), comprising administering a therapeutically effectiveamount of a compound of Formula I or a pharmaceutically acceptable salt,solvate or prodrug thereof, or a pharmaceutical composition comprisingthe compound of Formula I to patients in need thereof.

In a still further aspect, the present invention provides a use of acompound of Formula I or a pharmaceutically acceptable salt, solvate orprodrug thereof, or a pharmaceutical composition comprising the compoundof Formula I in the manufacture of a medicament for treating and/orpreventing diseases mediated by anaplastic lymphoma kinase (AKL).

A further aspect of the present invention is to provide a pharmaceuticalcomposition comprising a compound represented by Formula I or apharmaceutically acceptable salt thereof, for treating and/or preventingdiseases mediated by anaplastic lymphoma kinase (AKL).

In some embodiments of the present invention, diseases mediated byanaplastic lymphoma kinase (AKL) are cancer. The cancer is selected fromovarian cancer, cervical cancer, colorectal cancer, breast cancer,pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer,leukemia, lymphoma, Non-Hodgkin's lymphoma, stomach cancer, lung cancer,hepatocellular carcinoma, gastrointestinal stromal tumor, thyroidcancer, biliary duct cancer, endometrial cancer, renal cancer, anaplasialarge cell lymphoma, acute myeloid leukemia, multiple myeloma, melanomaand mesothelioma. The lung cancer is selected from non-small cell lungcancer, small cell lung cancer, lung adenocarcinoma, and lung squamouscell carcinoma.

The compound of Formula I or the pharmaceutically acceptable salt,solvate or prodrug thereof, or the pharmaceutical composition comprisingthe compound of Formula I according to the present invention can be alsofor use in the manufacture of a medicament for treating and/orpreventing cardiovascular diseases, inflammation, infection, immunediseases, cell proliferative diseases, viral diseases, metabolicdiseases and organ transplantation.

Related Definition

The term “pharmaceutically acceptable” refers to those compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof human beings and animals without excessive toxicity, irritation,allergic response, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The term “pharmaceutically acceptable salt” refers to a salt thatretains the biological effectiveness of the free acids and free bases ofa specific compound, which are not biologically or otherwiseundesirable. Examples of the pharmaceutically acceptable salt include,but not limited to, (1) acid addition salts such as, salts formed withinorganic acids such as hydrochloric acid, sulfuric acid, hydrobromicacid, nitric acid, phosphoric acid and the like, or salts formed withorganic acids such as malic acid, fumaric acid, maleic acid, benzoicacid, phenylacetic acid, succinic acid, tartaric acid, citric acid,methanesulfonic acid, ethanesulfonic acid, glycolic acid, cinnamic acid,pyruvate, formic acid, acetic acid, propionic acid, oxalic acid, malonicacid, acrylic acid, mandelic acid and the like; or (2) base additionsalts such as, salts formed with alkali metals such as lithium, sodium,potassium and the like, salts formed with alkaline earth metal such ascalcium, magnesium and the like, and salts formed with organic basessuch as ammonium, choline, diethanolamine, lysine, ethylenediamine,t-butylamine, t-octylamine, tris(hydroxymethyl)aminomethane, N-methylglucosamine, triethanolamine, dehydroabietylamine and the like.

The pharmaceutically acceptable salt of the present invention can besynthesized from a parent compound containing an acid or alkali group byconventional chemical methods. In general, such a salt is prepared by amethod of allowing these compounds in the form of free acid or base toreact with a stoichiometric amount of an appropriate base or acid inwater or an organic solvent, or a mixture thereof.

The term “solvate” or “solvates” includes hydrates and solvent additionforms and salts thereof, which are able to be formed by the compound ofFormula I. Examples of such forms are hydrates, alcoholates or the like.

If not specified, any atom of the compounds labeling-synthesized in thepresent invention will represent any one of stable isotopes of thisatom. When a position in the structure is defined as H, i.e., hydrogen(H-1), unless otherwise specifically stated, this position only containsnaturally occurring isotopes. Likewise, when a position in the structureis defined as D, i.e., deuterium (H-2), unless otherwise specificallystated, the amount of the isotope at this position is at least 3340times greater than that of naturally occurring isotopes (0.015%) (i.e.,at least 50.1% isotope deuterium is contained). When one or severalpositions in the structure of a compound labeling-synthesized aredefined as D, i.e., deuterium (H-2), the compound represented by thestructure can be at least 52.5%, at least 60%, at least 67.5%, at least75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least98.5%, at least 99%, and at least 99.5%. A deuterated ratio of thecompound labeling-synthesized in the present invention refers to a ratiovalue of the content of a labeled synthetic isotope to the content ofnaturally occurring isotopes. The deuterated ratio of each indicatedatom in the compound labeling-synthesized according to the presentinvention can be at least 3500 fold (52.5%), at least 4000 fold (60%),at least 4500 fold (67.5%), at least 5000 fold (75%), at least 5500 fold(82.5%), at least 6000 fold (90%), at least 6333.3 fold (95%), at least6466.7 fold (97%), at least 6566.7 fold (98.5%), at least 6600 fold(99%), at least 6633.3 fold (99.5%). Isotopologues in the presentinvention refers to compounds that differ merely by different isotopiccomposition in terms of chemical structure. The compoundslabeling-synthesized in the present invention have the same chemicalstructure and only have differences in isotope in atomic composition oftheir molecules. Therefore, the compound having deuterium at a specificposition labeling-synthesized in the present invention also containsvery few hydrogen isotopologue at this position. The amount of hydrogenisotopologue at a position in the compound labeling-synthesized in thepresent invention depends on many factors, including isotope deuteriumpurity of deuterated reagents (D₂O, D₂, NaBD₄, LiAID₄, etc.) andeffectiveness of the synthesis methods for introducing isotopedeuterium. However, as mentioned above, the total amount of hydrogenisotopologue at such a position will be less than 49.9%. The totalamount of hydrogen isotopologue at a position in a compoundlabeling-synthesized in the present invention will be less than 47.5%,40%, 32.5%, 25%, 17.5%, 10%, 5%, ₃%_(, 1)% or 0.5%.

In the present invention, any atom that is not specified as deuteriumexists at natural isotope abundance thereof.

The term “pharmaceutically acceptable carrier” refers to a carrier thatdoes not cause significant irritation to an organism and does notabrogate the biological activity and properties of the active compound.The “pharmaceutically acceptable carrier” refers to an inert materialthat is administered together with an active ingredient and facilitatesthe administration of the active ingredient, including but not limitedto, any glidants, sweeteners, diluents, preservatives, dyes/coloringagents, flavor enhancers, surfactants, wetting agents, dispersants,disintegrants, suspending agents, stabilizers, isotonic agents, solventor emulsifier. Non-limited examples of the carriers include calciumcarbonate, calcium phosphate, various carbohydrates and various kinds ofstarch, cellulose derivatives, gelatin, vegetable oils, polyethyleneglycol and the like. Other information about the carriers can refer toRemington: The Science and Practice of Pharmacy, 21st Ed., Lippincott,Williams & Wilkins (2005), the contents of which is incorporated hereinby reference.

The term “excipient” or “excipients” usually refers to a carrier,diluent and/or medium required for formulating an effectivepharmaceutical composition.

For a drug or pharmaceutical active agent, the term “effective amount”or “therapeutically effective amount” means a nontoxic but sufficientamount of the drug or agent to provide the desired effect. In the oraldosage forms of the present invention, an “effective amount” of oneactive substance in the composition refers to the amount of thatsubstance that is required to provide the desired effect when used incombination with the other active substance of the composition. Thedetermination of an effective amount varies from person to person,depending upon the age and general conditions of the subject, and alsodepending upon the specific active substance. A suitable effectiveamount in each individual case can be determined by those skilled in theart according to routine testing.

Unless otherwise indicated, all raw materials are commercial and willnot be further purified prior to being used. Silica gel (200-300 mesh)produced by Qingdao Haiyang Chemical Co., Ltd is employed in the columnchromatography used in the present invention. Thin layer chromatographyis produced by Qingdao MaKall Group Inc. Instruments used for NMRspectroscopy are BRUKER-300 and BRUKER-500 resonance spectrometers,tetramethylsilane (TMS=δ 0.00) as an internal standard for a chemicalshift, and the data of NMR spectroscopy is recorded in a format of:proton number, peak shapes (s, singlet; d, doublet; t, triplet; q,quartet; m, multiplet), coupling constant (in Hertz, Hz). AB SCIEXTriple TOF 4600 is used for mass spectrometry.

The following abbreviations are used in the present invention: Boc-represents t-butyloxycarbonyl; DMF represents N,N-dimethylformamide.

The compounds represented by Formula I of the present invention (forexample, in the situations that R₁ is deuterium, R₂ and R₃ aredeuterium, R₄ and R₅ are deuterium or R₈ is deuterium, particularly inthe situations that R₁ is deuterium, R₂ and R₃ are deuterium or R₈ isdeuterium, especially in the situations of the compounds in Examples)have better pharmacokinetic properties as compared to Brigatinib andhave an excellent inhibitory activity against anaplastic lymphoma kinase(ALK).

SPECIFIC EMBODIMENTS The present invention will be described by thefollowing examples in more details, which do not limit the presentinvention by any means.

It should be noted that in the following examples, the preparationmethods of the compounds are described by taking only I-1 (Example 1),I-2 (Example 3), I-3 (Example 5), I-4 (Example 6), I-6 (Example 7), 1-7(Example 8) and 1-9 (Example 9) as examples. However, since the presentinvention focuses on the deuterium-modified Brigatinib derivatives, themethods for preparing the compounds according to the present inventionare similar. Therefore, the compounds within the scope of the claims ofthe present invention can be prepared by using methods similar to thosedescribed in the Description of the present invention and the followingexamples.

EXAMPLE 1 Preparation of2-((5-chloro-2-((2-[D₃]methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphorus oxide (the compound of Formula I-1)

Step 1: Preparation of 4-fluoro-2-[D₃]methoxy-1-nitrobenzene (thecompound of Formula I-11)

5-fluoro-2-nitrophenol (15.7 g, 100 mmol), anhydrous potassium carbonate(13.8 g, 100 mmol) and acetone (150 mL) were respectively added in a 250mL three-necked flask and stirred at room temperature for 100 minutes,and then deuterated iodomethane (6.2 mL, 100mmol) was slowly addeddropwise. After the dropwise addition, the mixture was heated to refluxand react for 9 hours. After the reaction was completed, the reactionsolution was cooled down to room temperature and filtered by suction.The filtrate was evaporated under reduced pressure to remove thesolvent, added with 10% sodium hydroxide aqueous solution (100 mL),stirred vigorously, extracted with ethyl acetate (100 mL×3), dried overanhydrous sodium sulfate and evaporated under reduced pressure to removethe solvent, to give 4-fluoro-2-[D₃]methoxy-1-nitrobenzene (17.7 g)with >98% of D₃ content.

¹H-NMR (300 MHz, CDCl₃): δ=7.97-7.92 (dd, J=6.0, 8.9 Hz, 1H), 6.81-6.69(m, 2H).

Step 2: Preparation of1-(1-(3-[D₃]methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine(the compound of Formula I-12)

A mixture of 4-fluoro-2-[D₃]methoxy-1-nitrobenzene (2.12 g, 12.17 mmol),1-methyl-4-(4-piperidinyl)piperazine (2.23 g, 12.17 mmol) and anhydrouspotassium carbonate (3.37 g, 24.34 mmol) in DMF (20 mL) was heated to120° C. and reacted for 6 hours. After the reaction was completed, thereaction solution was cooled, filtered by suction, and evaporated underreduced pressure to remove the solvent, followed by addingdichloromethane (60 mL) and water (30 mL), and stirring to separatelayers. The aqueous layer was extracted with dichloromethane (30 mL×6).The organic phase was combined, washed with saturated brine (60 mL),dried over anhydrous sodium sulfate, filtered by suction and evaporatedunder reduced pressure to remove the solvent, to give1-(1-(3-[D₃]methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine(2.95 g, 72.0% yield), with >98% of D₃ content.

¹H-NMR (300MHz, CDCl₃): δ=7.98 (d, J=9.3 Hz, 1H), 6.41 (dd, J=2.4, 9.3Hz, 1H), 6.30 (d, J=2.0 Hz, 1H), 3.94 (d, J=13.2 Hz, 2H), 2.96 (t,J=12.0 Hz, 2H), 2.62-2.45 (m, 9H), 2.29 (s, 3H), 1.96 (d, J=12.5 Hz,2H), 1.63-1.54 (m, 2H).

HRMS (ESI, [M+H]⁺) m/z: 338.2254.

Step 3: Preparation of2-[D₃]methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (thecompound of Formula I-13)

1-(1-(3-[D₃]methoxy-4-nitrophenyl)piperidin-4-yl)-4-methylpiperazine(0.59 g, 1.7 mmol) was dissolved in anhydrous methanol (30 mL) and addedwith 10% Pd—C (0.12 g), and hydrogenation reaction was allowed toproceed overnight at room temperature. After the reaction was completed,the reaction solution was filtered by suction and evaporated underreduced pressure to remove the solvent, to give2-[D₃]methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (0.45g, 86.5% yield), with >98% of D₃ content.

¹H-NMR (300 MHz, CDCl₃): δ=6.62 (d, J=8.3 Hz, 1H), 6.51 (d, J=2.4 Hz,1H), 6.41 (dd, J=2.4, 8.4 Hz, 1H), 3.53-3.49 (m, 3H), 2.83-2.33 (m,10H), 2.29 (s, 3H), 1.92 (d, J=12.2 Hz, 2H), 1.77-1.64 (m, 2H).

HRMS (ESI, [M+H]⁺) m/z: 308.2525.

Step 4: Preparation of(2-((5-chloro-2-((2-[D₃]methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphorus oxide (the compound of Formula I-1)

2-[D₃]methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (1.25g, 4.06 mmol), (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (the compound of Formula IV) (0.92 g, 2.90 mmol), 14%hydrogen chloride-ethanol (7.5 g, 29 mmol) and ethylene glycolmonomethyl ether (22 mL) were respectively added in a 35 mL pressuretubing, heated in a microwave to 120° C. and reacted for 5.5 hours.After the reaction was completed, the reaction solution was cooled downto room temperature and evaporated under reduced pressure to remove thesolvent. The residue was dissolved in dichloromethane (60 mL) andadjusted to alkaline pH by adding saturated sodium carbonate solution.The resulting solution was separated. The organic phase was washed withsaturated brine (30 mL), dried over anhydrous sodium sulfate, andevaporated under reduced pressure to remove the solvent. The residueobtained was subjected to silica gel column chromatography (mobilephase, dichloromethane:methanol:triethylamine=300:30:1.5) to give acrude product. The crude product was beaten with ethyl acetate (10 mL)to give (2-((5-chloro-2-((2-[D₃]methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphorus oxide (0.18 g, 11.0% yield), with >98% of D₃ content.

¹H-NMR (300 MHz, CDCl₃): δ=10.80 (s, 1H), 8.62 (dd, J=4.4, 8.2 Hz, 1H),8.09-8.08 (m, 2H), 7.47 (dd, J=7.7, 8.0 Hz, 1H), 7.31-7.25 (m, 1H), 7.11(dd, J=7.4, 7.0 Hz, 1H), 6.54 (s, 1H), 6.48 (dd, J=1.4, 8.4 Hz, 1H),3.65 (d, J=12.2 Hz, 2H), 2.73-2.41 (m, 11H), 2.37 (s, 3H), 1.95 (d,J=11.2 Hz, 2H), 1.85, 1.80 (2s, 6H), 1.73-1.66 (m, 2H).

¹³C-NMR (75 MHz, CDCl₃): δ=157.76, 155.87, 154.93, 149.29, 147.48,143.90, 143.87, 132.33, 132.30, 129.52, 129.37, 123.10, 123.01, 122.44,122.27, 122.09, 120.58, 119.55, 108.36, 105.99, 101.01, 61.78, 55.27,50.46, 48.78, 45.83, 28.19, 19.02, 18.08.

HRMS (ESI, [M+H]⁺) m/z: 587.2861.

EXAMPLE 2 Preparation of(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethyl phosphorus oxide(the compound of Formula IV)

(2-aminophenyl)dimethyl phosphorus oxide (8.76 g, 51.81 mmol),2,4,5-trichloropyrimidine (14.92 g, 81.35 mmol), anhydrous potassiumcarbonate (22.49 g, 162.29 mmol) and N,N-dimethylformamide (50 mL) wereadded in a 100 mL single-necked flask, and the mixture was heated to 60°C. and reacted for 5 hours. After the reaction was completed, thereaction solution was cooled down to room temperature, added with water(30 mL) and extracted with dichloromethane (100 mL×3), washed withsaturated brine (100 mL), dried over anhydrous sodium sulfate, filteredby suction, and evaporated under reduced pressure to remove the solvent.The resulting crude product was subjected to silica gel columnchromatography (mobile phase, dichloromethane:methanol=40:1) to give(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethyl phosphorus oxide(11.3 g, 69.0% yield).

¹H-NMR (300 MHz, CDCl₃): δ=11.55 (s, 2H), 8.67 (dd, J=4.4, 8.5 Hz, 1H),8.22 (s, 1H), 7.59 (dd, J=7.7, 8.1 Hz, 1H), 1.86 (s, 3H), 1.82 (s, 3H).

¹³C-NMR (75 MHz, CDCl₃): δ=156.85, 155.10, 133.05, 133.03, 129.77,129.63, 123.56, 123.40, 122.18, 122.09, 19.28, 18.33.

HRMS (ESI, [M+H]⁺) m/z: 316.0175.

EXAMPLE 3 Preparation of(2-((5-chloro-2-((2-methoxy-4-(4-(4-[D₃]methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphorus oxide (the compound of Formula I-2)

Step 1: Preparation of 4-fluoro-2-methoxynitrobenzene (the compound ofFormula I-21)

5-fluoro-2-nitrophenol (10 g, 63.65 mmol), potassium carbonate (8.8 g,63.65 mmol) and acetone (100 mL) were added in a 250 mL three-neckedflask and stirred at room temperature for 30 minutes under theprotection of nitrogen gas. Iodomethane (9.03 g, 63.65 mmol) was thenslowly added dropwise thereto, and the mixture was warmed up to 60° C.and reacted overnight. After the reaction was completed, the reactionsolution was added with water (200 mL), extracted with ethyl acetate(100 mL×4), washed with 1M sodium hydroxide (100 mL×3) and saturatedbrine (100 mL×2) successively, dried over anhydrous sodium sulfate,filtered by suction and evaporated under reduced pressure to remove thesolvent, to give 4-fluoro-2-methoxynitrobenzene (10.8 g, 99.1% yield).

Step 2: Preparation of 1-(3-methoxy-4-nitrophenyl)piperidin-4-one (thecompound of Formula I-22)

4-fluoro-2-methoxynitrobenzene (3.4 g, 20 mmol), piperidonehydrochloride monohydrate (3.4 g, 22 mmol), anhydrous potassiumcarbonate (6.9 g, 50 mmol) and DMF (400 mL) were respectively added in a100 mL single-necked flask, and the mixture was heated to 75° C. andreacted for 18 hours. After the reaction was completed, the reactionsolution was cooled down to room temperature, filtered by suction andevaporated under reduced pressure to remove the solvent. The residue wasdissolved in dichloromethane (600 mL), washed with water (60 mL) andsaturated brine (60 mL) respectively, dried over anhydrous sodiumsulfate, filtered by suction and evaporated under reduced pressure toremove the solvent, to give a crude product. The crude product wasbeaten with n-hexane (200 mL) and filtered by suction to give1-(3-methoxy-4-nitrophenyl)piperidin-4-one (2.12 g, 42.4% yield).

¹H-NMR (300 MHz, CDCl₃): δ=8.04 (d, J=9.2 Hz, 1H), 6.46 (dd, J=9.2, 2.3Hz, 1H), 6.38 (d, J=2.2 Hz, 1H), 3.97 (s, 3H), 3.79 (t, J=6.0 Hz, 4H),2.65 (t, J=6.0 Hz, 4H).

Step 3: Preparation of1-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)-4-[D₃]methylpiperazine(the compound of Formula I-23)

1-(3-methoxy-4-nitrophenyl)piperidin-4-one (2.20 g, 8.8 mmol) wasdissolved in 1,2-dichloroethane (30 mL), and then anhydrous magnesiumsulfate (6.0 g), acetic acid (0.53 mL, 8.8 mmol) and1-[D₃]methylpiperazine (1.80 g, 17.6 mmol) were respectively addedthereto, followed by stirring at room temperature for 1 hour. Sodiumtriacetoxyborohydride (2.24 g, 1.2 mmol) was added portionwise in an icebath, and the mixture was heated to room temperature and reacted for 5hours after addition. After the reaction was completed, the reactionsolution was added with solid sodium carbonate (6 g), stirred for 30minutes and filtered by suction. The filter cake was washed withdichloromethane (2×30 mL), further washed with saturated sodiumcarbonate aqueous solution (30 mL) and saturated brine (60 mL)respectively, dried over anhydrous sodium sulfate, filtered by suctionand evaporated under reduced pressure to remove the solvent, to give acrude product. The crude product was subjected to silica gel columnchromatography (mobile phase, dichloromethane:methanol=20:1 to 6:1) togive1-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)-4-[D₃]methylpiperazine(1.17 g, 39.4% yield), with >98% of D₃ content.

¹H-NMR (300 MHz, CDCl₃): δ=7.99 (d, J=9.5 Hz, 1H), 6.41 (dd, J=2.5, 9.5Hz, 1H), 6.31 (d, J=2.5 Hz, 1H), 3.96-3.93 (m, 5H), 2.96 (td, J=2.5,12.5 Hz, 2H), 2.63-2.4 (m, 9H), 1.98 (d, J=12.5 Hz, 2H), 1.63 (qd,J=3.5, 12.5 Hz, 2H).

HRMS (ESI, [M+H]⁺) m/z: 338.2201.

Step 4: Preparation of2-methoxy-4-(4-(4-[D3]methylpiperazin-1-yl)piperidin-1-yl)aniline (thecompound of Formula I-24)

1-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)-4-[D₃]methylpiperazine(1.12 g, 3.3 mmol) was dissolved in anhydrous methanol (25 mL) and addedwith 10% Pd—C (0.11g), and hydrogenation reaction was allowed to proceedovernight at room temperature. After the reaction was completed, thereaction solution was filtered by suction and evaporated under reducedpressure to remove the solvent, to give2-methoxy-4-(4-(4-[D₃]methylpiperazin-1-yl)piperidin-1-yl)aniline (0.97g, 96.0% yield), with >98% of D₃ content.

¹H-NMR (300 MHz, CDCl₃): δ=6.65 (d, J=8.0 Hz, 1H), 6.54 (d, J=2.5 Hz,1H), 6.43 (dd, J=2.0, 8.5 Hz, 1H), 3.85 (s, 3H), 3.53 (d, J=12.5 Hz,2H), 2.65-2.34 (m, 11H), 1.94 (d, J=12 Hz, 2H), 1.73 (qd, J=3.5, 12.5Hz, 2H).

HRMS (ESI, [M+H]⁺) m/z: 308.2466.

Step 5: Preparation of(2-((5-chloro-2-((2-methoxy-4-(4-(4-[D₃]methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethyl phosphorus oxide (thecompound of Formula I-2)

As Step 4 in Example 1,(2-((5-chloro-2-((2-methoxy-4-(4-(4-[D₃]methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethyl phosphorus oxide (0.45 g,32.4% yield) with >98% of D₃ content was obtained.

¹H-NMR (300 MHz, CDCl₃): δ=10.80 (s, 1H), 8.62 (dd, J=4.3, 8.3 Hz, 1H),8.09-8.08 (m, 2H), 7.47 (dd, J=7.6, 7.7 Hz, 1H), 7.31-7.27 (m, 1H), 7.11(dd, J=6.5, 7.2 Hz, 1H), 6.55 (s, 1H), 6.48 (d, J=8.7 Hz, 1H), 3.86 (s,3H), 3.65 (d, J=11.7 Hz, 2H), 2.70-2.41 (m, 11H), 1.96 (d, J=11.5 Hz,2H), 1.86,1.80 (2s, 6H), 1.74-1.66 (m, 2H).

¹³C-NMR (75 MHz, CDCl₃): δ=157.75, 155.85, 154.89, 149.31, 147.46,143.87, 143.84, 132.28, 129.49, 129.34, 123.08, 122.98, 122.41, 122.25,122.06, 120.82, 120.60, 119.55, 108.36, 105.96, 101.00, 61.75, 55.28,55.13, 50.40, 48.71, 28.16, 18.99, 18.04.

HRMS (ESI, [M+H]⁺) m/z: 587.2780.

EXAMPLE 4 Preparation of 1-[D₃]methylpiperazine

Step 1: Preparation of 4-methylbenzenesulfonic acid [D₃]methyl ester

Granulated sodium hydroxide (27.7 g, 693.7 mmol) and water (50 mL) wereadded in a 500 mL three-necked flask and dissolve after stirring, andthe solution was cooled down to 0° C. A solution of p-toluenesulfonylchloride (31.74 g, 166.48 mmol) in anhydrous tetrahydrofuran (50 mL) wasthen slowly added dropwise thereto at 0° C., and the resulting solutionwas warmed up to room temperature and stirred overnight after dropwiseaddition. After the reaction was completed, the reaction solution wasneutralized by slowly adding dropwise with acetic acid (31.7 g) at 20°C., extracted with ethyl acetate (3×100 mL), washed with saturatedsodium carbonate aqueous solution (100 mL) and saturated brine (100 mL)respectively, dried over anhydrous sodium sulfate and evaporated underreduced pressure to remove the solvent, to give 4-methylbenzenesulfonicacid [D₃]methyl ester (20.62 g, 78.5% yield), with >98% of D₃ content.

¹H-NMR (300 MHz, CDCl₃): δ=7.78 (d, J=8.0 Hz, 2H), 7.36 (d, J=7.9 Hz,2H), 2.45 (s, 3H).

Step 2: Preparation of 1-benzyl-4-[D₃]methylpiperazine

1-benzylpiperazine (17.63 g, 100 mmol) and dried tetrahydrofuran (70 mL)were added in a 250 mL single-necked flask, cooled down to 0° C., addedportionwise with 60% sodium hydride (4.0 g, 100 mmol) and stirred atroom temperature for 30 minutes. After cooling down to 0° C., a solutionof 4-methylbenzenesulfonic acid [D₃]methyl ester (9.46 g, 50 mmol) intetrahydrofuran (10 mL) was slowly added dropwise thereto, followed bynaturally warming up to room temperature and stirred overnight. Afterthe reaction was completed, the reaction solution was filtered bysuction. The filter cake was washed with ethyl acetate (3×20 mL), andevaporated under reduced pressure to remove the solvent, to give a crudeproduct. 1-benzyl-4-[D₃]methylpiperazine (5.2 g, 54.7% yield) with >98%of D₃ content was then obtained by column chromatography.

¹H-NMR (300 MHz, CDCl₃): δ=7.31-7.23 (m, 5H), 3.5 (s, 2H), 2.72-2.26 (m,8H).

HRMS (ESI, [M+H]⁺) m/z 194.1683.

Step 3: Preparation of 1-[D₃]methylpiperazine

1-benzyl-4-[D₃]methylpiperazine (5.2 g, 26.77 mmol) was dissolved inanhydrous methanol (30 mL) and added with 10% Pd—C (0.8 g), andhydrogenation reaction was allowed to proceed at 40° C. for 12 hours.After cooling down to room temperature, the reaction solution wasfiltered by suction and re-added with 10% Pd—C (0.8 g), and additionalhydrogenation reaction were performed at 40° C. for 12 hours. Aftercooling, the reactant was filtered by suction and evaporated underreduced pressure at 40° C. to remove the solvent, to give1-[D₃]methylpiperazine (3.38 g, 100% yield), with >98% of D₃ content.

HRMS (ESI, [M+H]⁺) m/z:104.1247.

EXAMPLE 5 Preparation of(2-((5-chloro-2-((2-[D₃]methoxy-4-(4-(4-[D₃]methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphorus oxide (the compound of Formula I-3)

Step 1: Preparation of 1-(3-[D₃]methoxy-4-nitrophenyl)piperidin-4-one(the compound of Formula I-31)

4-fluoro-2-[D₃]methoxy-1-nitrobenzene (3.48 g, 20 mmol), 4-piperidonehydrochloride hydrate (3.38 g, 22 mmol) and anhydrous potassiumcarbonate (6.91 g, 50 mmol) were dissolved in DMF (50 mL), heated to 75°C. and reacted overnight.

After the reaction was completed, the reaction solution was cooled downto room temperature and filtered by suction. The filter cake was washedwith dichloromethane (5 mL×3) and evaporated under reduced pressure toremove the solvent to give a crude product. The crude product was beatenby adding methanol (20 mL), filtered and dried to give1-(3-[D₃]methoxy-4-nitrophenyl)piperidin-4-one (2.07 g, 40.9% yield),with >98% of D₃ content.

¹H-NMR (300 MHz, CDCl₃): δ=7.99 (d, J=9.2 Hz, 1H), 6.42 (d, J=9.2 Hz,1H), 6.33 (s, 1H), 3.81-3.77 (m, 4H), 2.65-2.61 (m, 4H).

HRMS (ESI, [M+H]⁺) m/z: 590.2879.

Step 2: Preparation of1-(1-(3-[D₃]methoxy-4-nitrophenyl)piperidin-4-yl)-4-[D₃]methylpiperazine(the compound of Formula I-32)

As Step 3 in Example 3, 1-(3-[D₃]methoxy-4-nitrophenyl)piperidin-4-one(1.52 g, 6 mmol) reacted with 1-[D₃]methylpiperazine to give1-(1-(3-[D₃]methoxy-4-nitrophenyl)piperidin-4-yl)-4-[D₃]methylpiperazine(0.6 g, 30.0% yield), with >98% of D₆ content.

¹H-NMR (300 MHz, CDCl₃): δ=8.00 (d, J=9.5 Hz, 1H), 6.43 (dd, J=2.5, 9.5Hz, 1H), 6.30 (d, J=2.0 Hz, 1H), 3.95 (d, J=13.0 Hz, 2H), 2.98 (t,J=12.0 Hz, 2H), 2.64-2.49 (m, 9H), 1.98 (d, J=12.5 Hz, 2H), 1.66-1.58(m, 2H).

HRMS (ESI, [M+H]⁺) m/z: 341.2790.

Step 3: Preparation of2-[D₃]methoxy-4-(4-(4-[D₃]methylpiperazin-1-yl)piperidin-1-yl)aniline(the compound of Formula I-33)

As Step 3 in Example 1,1-(1-(3-[D₃]methoxy-4-nitrophenyl)piperidin-4-yl)-4-[D₃]methylpiperazine(0.6 g, 1.7 mmol) was reduced to give2-[D₃]methoxy-4-(4-(4-[D₃]methylpiperazin-1-yl)piperidin-1-yl)aniline(0.5 g), with >98% of D₆ content.

HRMS (ESI, [M+H]⁺) m/z: 311.2704.

Step 4: Preparation of(2-((5-chloro-2-((2-[D₃]methoxy-4-(4-(4-[D₃]methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphorus oxide (the compound of Formula I-3)

As Step 4 in Example 1,2-[D₃]methoxy-4-(4-(4-[D₃]methylpiperazin-1-yl)piperidin-1-yl)anilinereacted with (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphorus oxide to give(2-((5-chloro-2-((2-[D₃]methoxy-4-(4-(4-[D₃]methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphorus oxide (0.45 g, 20.7% yield), with >98% of D₆ content.

¹H-NMR (300 MHz, CDCl₃): δ=10.80 (s, 1H), 8.62 (dd, J=4.4, 8.4 Hz, 1H),8.09-8.08 (m, 2H), 7.47 (dd, J=7.7, 8.0 Hz, 1H), 7.31-7.25 (m, 1H), 7.11(dd, J=6.5, 6.8 Hz, 1H), 6.54 (d, J=9.2 Hz, 1H), 6.48 (dd, J=1.7, 8.8Hz, 1H), 3.65 (d, J=12.1 Hz, 2H), 2.77-2.43 (m, 11H), 2.02 (d, J=12.9Hz, 2H), 1.85, 1.80 (2s, 6H), 1.76-1.72 (m, 2H).

¹³C-NMR (75 MHz, CDCl₃): δ=157.74, 155.86, 154.91, 149.28, 147.35,143.87, 132.32, 132.29, 129.53, 129.38, 123.09, 123.00, 122.46, 122.29,122.19, 120.82, 120.56, 119.56, 108.40, 106.01, 101.05, 61.82, 54.79,50.41, 48.31, 28.08, 19.01, 18.06.

HRMS (ESI, [M+H]⁺) m/z: 590.2879.

EXAMPLE 6 Preparation of(2-((5-chloro-2-((2-methoxy-4-(4-(4-methyl[2,2,6,6-D₄]piperazin-1-yl)piperidine-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphorus oxide (the compound of Formula I-4)

Step 1: Preparation of 1-methyl[3,3,5,5-D₄]piperazine

1-methylpiperazine (20 g, 199.8 mmol) was added in a 250 mL three-neckedflask, cooled down to 0° C., slowly added dropwise with 2M hydrochloricacid (233.8 mmol, 111.9 mL) and stirred for 20 minutes. Sodium nitrite(16.27 g, 235.76 mmol) was dissolved in 40 mL water, added dropwiseslowly in the three-necked flask at 0° C., stirred at room temperatureovernight, and further reacted at 35° C. for 2 hours. After the reactionwas completed, the reaction solution was adjusted to alkaline pH usingsodium hydroxide, extracted with dichloromethane (100 mL×10), dried overanhydrous sodium sulfate, and evaporated under reduced pressure toremove the solvent, to give 1-methyl-4-nitrosopiperazine (27 g).

Heavy water (425 mL) and sodium methoxide (32.38 g, 599.4 mmol) wereadded into the above crude product and reacted at 80° C. for 100 hours,concentrated, then extracted with dichloromethane (100 mL×10), driedover anhydrous sodium sulfate, and evaporated under reduced pressure toremove the solvent, to give 1-methyl-nitroso[3,3,5,5-D₄]piperazine(15.68 g).

Heavy water (300 mL) and sodium methoxide (19.68 g, 364.4 mmol) wereadded into the above crude product and reacted at 80° C. for 40 hours.The reaction solution was then cooled down to 0° C. and addedportionwise with Al—Ni alloy (76.30 g) in batches, and the reaction wasinitiated at room temperature and performed overnight at 0° C. After thereaction was completed, the reaction solution was filtered by suctionand the mother liquid was distilled under reduced pressure. The obtainedfractions were adjusted to be acidic by using hydrochloric acid,evaporated under reduced pressure to remove water and beaten withethanol, to give 1-methyl[3,3,5,5-D₄]piperazine hydrochloride (14.13 g,40.8% yield). The above hydrochloride (6.0 g, 33.86 mmol), anhydroussodium methoxide (5.49 g, 101.58 mmol) and anhydrous methanol (60 mL)were added in a 250 mL single-necked flask and heated to reflux for 5hours. After the reaction was completed, the reaction solution wascooled down to room temperature, filtered by suction and evaporatedunder reduced pressure to remove the solvent, to give a crude product of1-methyl[3,3,5,5-D₄]piperazine (3.94 g) with 96% of D₄ content, whichwas used directly in the next step.

HRMS (ESI, [M+H]⁺) m/z: 105.1327.

Step 2: Preparation of1-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methyl[2,2,6,6-D₄]piperazine(the compound of Formula I-41)

As Step 3 in Example 3, 1-(3-methoxy-4-nitrophenyl)piperidin-4-one (2.50g, 10 mmol) reacted with 1-methyl[4,4,5,5-D₄]piperazine (2.12 g, 20mmol) to give1-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methyl[2,2,6,6-D₄]piperazine(0.7 g, 20.6% yield), with 96% of D₄ content.

¹H-NMR (300 MHz, CDCl₃): δ=7.97 (d, J=9.5 Hz, 1H), 6.40 (dd, J=2.1, 9.4Hz, 1H), 6.30 (d, J=2.1 Hz, 1H), 3.94-3.80 (m, 6H), 2.96-2.45 (m, 6H),2.29 (s, 3H), 1.97 (d, J=12.0 Hz, 2H), 1.67-1.54 (m, 2H).

HRMS (ESI, [M+H]⁺) m/z: 339.2216.

Step 3: Preparation of2-methoxy-4-(4-(4-methyl[2,2,6,6-D₄]piperazin-1-yl)piperidin-1-yl)aniline(the compound of Formula I-42)

As Step 3 in Example 1,1-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methyl[2,2,6,6-D₄]piperazine(0.70 g) was reduced by hydrogenation to give2-methoxy-4-(4-(4-methyl[2,2,6,6-D₄]piperazin-1-yl)piperidin-1-yl)aniline(0.63 g, 98.9% yield), with 96% of D₄ content.

¹H-NMR (300 MHz, CDCl₃): δ=6.62 (d, J=8.3 Hz, 1H), 6.51 (s, 1H), 6.41(dd, J=1.5, 8.2 Hz, 1H), 3.83 (s, 3H), 3.53-3.49 (m, 3H), 2.65-2.46 (m,6H), 2.29 (s, 3H), 1.92 (d, J=12.0 Hz, 2H), 1.77-1.64 (m, 2H).

HRMS (ESI, [M+H]⁺) m/z: 309.2585.

Step 4: Preparation of (2-((5-chloro-2-((2-methoxy-4-(4-(4-methyl[2,2,6,6-D₄] piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphorus oxide (the compound of Formula I-4)

As Step 4 in Example 1,2-methoxy-4-(4-(4-methyl[2,2,6,6-D₄]piperazin-1-yl)piperidin-1-yl)aniline(0.6 g, 1.94 mmol) reacted with(2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethyl phosphorus oxide(0.4 g^(,) 1.27 mmol) to give (2-((5-chloro-2-((2-methoxy-4-(4-(4-methyl[2,2,6,6-D₄] piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphorus oxide (0.32 g, 42.8% yield), with 96% of D₄ content.

₁H-NMR (300 MHz, CDCl₃): δ=10.79 (s, 1H), 8.62 (dd, J=4.3, 8.3 Hz, 1H),8.08-8.06 (m, 2H), 7.48(dd, J=7.5, 8.1 Hz, 1H), 7.31-7.24 (m, 1H), 7.11(dd, J=6.6, 7.2 Hz, 1H), 6.54 (s, 1H), 6.49 (d, J=8.8 Hz, 1H), 3.86 (s,3H), 3.65 (d, J=12.2 Hz, 2H), 2.73-2.41 (m, 7H), 2.33 (s, 3H), 1.96 (d,J=11.2 Hz, 2H), 1.84, 1.80 (2s, 6H), 1.73-1.69 (m, 2H).

¹³C-NMR (75 MHz, CDCl₃): δ=157.76, 155.87, 154.91, 149.31, 147.48,143.88, 143.84, 132.31, 132.28, 129.50, 129.35, 123.10, 123.00, 122.43,122.27, 122.09, 122.06, 120.60, 108.37, 105.97, 101.02, 61.69, 55.59,55.07, 50.42, 45.85, 28.19, 19.00, 18.05.

HRMS (ESI, [M+H]⁺) m/z: 588.2855.

EXAMPLE 7 Preparation of(2-((5-chloro-2-((2-methoxy-4-(4-(4-methyl[D₈]piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-1-yl)amino)phenyl)dimethylphosphorus oxide (the compound of Formula I-6)

Step 1: Preparation of 1-t-butoxycarbonyl[D₈]piperazine

[D₈]piperazine hydrochloride (5.0 g, 29.92 mmol), sodium hydroxide (1.3g, 32.5 mmol), anhydrous methanol (50 mL) were added in a 100 mLsingle-necked flask and heated to reflux for 3 hours. After the reactionwas completed, the reaction solution was cooled down to room temperatureand filtered by suction to remove inorganic salts. The filtrate wasevaporated to dryness, and the residue was added with water (30 mL) andt-butanol (30 mL), and dissolved completely by stirring. In an ice bath,2.5N sodium hydroxide solution (30 mL, 75 mmol) was added and a solutionof Boc anhydride in t-butanol (20 mL, 14.96 mmol) was then slowly addeddropwise, followed by stirring overnight at room temperature. Next day,the reaction solution was evaporated under reduced pressure to removet-butanol and filtered by suction. The filtrate was extracted withdichloromethane (50 mL×2), dried over anhydrous sodium sulfate, filteredby suction and evaporated under reduced pressure to remove the solvent,to give 1-t-butoxycarbonyl[D₈]piperazine (2.6 g, 44.7% yield), with 96%of D₈ content.

HRMS ESI, (M+Na) m/z: 195.1944.

Step 2: Preparation of 1-t-butoxycarbonyl-4-methyl[D₈]piperazine

In an ice bath, 60% sodium hydrogen (0.64 g, 26.76 mmol) was slowlyadded portionwise to a solution of 1-t-butoxycarbonyl[D₈]piperazine (2.6g, 13.38 mmol) in tetrahydrofuran (26 mL), and after addition, the icebath was removed. A solution of methyl p-toluenesulfonate (2.78 g, 14.72mmol) in tetrahydrofuran (20 mL) was slowly added dropwise, followed bystirring overnight at room temperature. After the reaction wascompleted, the reaction solution was filtered by suction to give afilter cake. The filter cake was washed with tetrahydrofuran (5 mL×3)and tetrahydrofuran was then removed by evaporation under reducedpressure. The residue was added with water (25 mL), extracted withdichloromethane (25 mL×2), washed with saturated brine (20 mL), driedover anhydrous sodium sulfate, filtered by suction and evaporated underreduced pressure to remove the solvent, to give1-t-butoxycarbonyl-4-methyl[D₈]piperazine (2.26 g, 81% yield), with 96%of D₈ content.

Step 3: Preparation of 1-methyl[D₈]piperazine

1-t-butoxycarbonyl-4-methyl[D₈]piperazine (2.26 g, 10.85 mmol) wasdissolved in 10 mL isopropanol, followed by adding an isopropanolhydrochloride solution (5.3 mL, 65.1 mmol) in an ice bath. The reactionsolution was warmed up to 50° C. After the reaction was completed, thereaction solution was filtered by suction and the filter cake was driedunder vacuum to give 1-methyl[D₈]piperazine hydrochloride (1.43 g, 72.7%yield). The hydrochloride was then treated with potassium carbonate togive 1-methyl[D₈]piperazine in the free form, with 96% of D₈ content.

¹H-NMR (500MHz, D2O): δ=2.96 (s, 3H), 1.08-1.09 (d, J=6.0 Hz, 1H).

HRMS (ESI, [M+H]⁺) m/z: 109.1679.

Step 4: Preparation of1-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methyl[D₈]piperazine(the compound of Formula I-61)

As Step 3 in Example 3,1-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methyl[D₈]piperazine(0.78 g, 22% yield) with 96% of D₈ content was obtained.

¹H-NMR (500 MHz, CDCl₃): δ=8.00 (d, J=9.5 Hz, 1H), 6.42 (dd, J=2.0, 9.5Hz, 1H), 6.31 (d, J=2.0 Hz, 1H), 3.94-3.80 (m, 5H), 2.98 (t, J=12.0 Hz,2H), 2.53-2.49 (m, 1H), 2.33 (s, 3H), 1.98 (d, J=12.5 Hz, 2H), 1.66-1.58(m, 2H).

HRMS (ESI, [M+H]⁺) m/z: 343.2577.

Step 5: Preparation of2-methoxy-4-(4-(4-methyl[D₈]piperazin-1-yl)piperidin-1-yl)aniline (thecompound of Formula I-62)

As Step 4 in Example 3, 2-methoxy-4-(4-(4-methyl[D₈]piperazin-1-yl)piperidin-1-yl)aniline (0.54g, 73.0% yield) with 96%of D₈ content was obtained.

¹H-NMR (500 MHz, CDCl₃): δ=6.65 (d, J=8.0 Hz, 1H), 6.54 (d, J=1.5 Hz,1H), 6.43 (dd, J=2.0, 8.5 Hz, 1H), 3.85 (s, 3H), 3.53 (d, J=12.0 Hz,2H), 2.63 (t, J=12 Hz, 2H), 2.61-2.33 (s, m, 1H), 2.32 (s, 3H), 1.94 (d,J=12.0 Hz, 2H), 1.77-1.69 (m, 2H).

HRMS (ESI, [M+H]⁺) m/z: 313.2829.

Step 6: Preparation of(2-((5-chloro-2-((2-methoxy-4-(4-(4-methyl[D₈]piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethyl phosphorus oxide (thecompound of Formula I-6)

As Step 4 in Example 1,(2-((5-chloro-2-((2-methoxy-4-(4-(4-methyl[D₈]piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphorus oxide (0.18 g, 26.7% yield) with 92.3% of D₈ content wasobtained.

1H-NMR (500 MHz, CDCl₃): δ=10.82 (s, 1H), 8.64 (dd, J=4.5, 8.0 Hz, 1H),8.11 (s, 1H), 8.10 (s, 1H), 7.51 (dd, J=7.5, 8.1 Hz, 1H), 7.32-7.27 (m,1H), 7.14 (d, J=1.5 Hz, 1H), 6.56 (d, J=2.5 Hz, 1H), 6.50 (dd, J=2.5,8.5 Hz, 1H), 3.88 (s, 3H), 3.67 (d, J=12.0 Hz, 2H), 2.72 (t, J=10.0 Hz,2H), 2.77-2.69 (m, 1H), 2.38 (s, 3H), 1.98 (d, J=12.0 Hz, 2H), 1.86,1.84 (2s, 6H), 1.78-1.73 (m, 2H).

¹³C-NMR (125 MHz, CDCl₃): δ=157.78, 155.91, 154.97, 149.32, 147.45,143.93, 132.37, 129.55, 129.46, 123.12, 122.46, 122.36, 122.20, 120.58,119.83, 108.45, 106.06, 101.11, 61.80, 55.64, 50.50, 45.66, 28.20,18.88, 18.31.

HRMS (ESI, [M+H]⁺) m/z: 592.3148.

EXAMPLE 8 Preparation of(2-((5-chloro-2-((2-methoxy-4-(4-(4-[D₃]methyl[3,3,5,5-D₄]piperazin-1-yl))piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphorus oxide (the compound of Formula I-7)

Step 1: Preparation of 1-benzyl-4-[D₃]methylpiperazine

As Step 1 in Example 4, 1-benzyl-4-[D₃]methyl[3,3,5,5-D₄]piperazine (4.6g, 34.9% yield) with 93.1% of D₇ content was obtained.

Step 2: Preparation of 1-[D₃]methyl[3,3,5,5-D₄]piperazine

As Step 2 in Example 4, 1-[D₃]methyl[3,3,5,5-D₄]piperazine (2.49 g, 100%yield) with 93% of D₇ content was obtained.

HRMS (ESI, [M+H]⁺) m/z: 108.1540.

Step 3: Preparation of1-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)-4-[D₃]methyl[3,3,5,5-D₄]piperazine(the compound of Formula I-71)

As Step 3 in Example 3,1-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)-4-[D₃]methyl[3,3,5,5-D₄]piperazine(0.94 g, 24.1% yield) with 93% of D₇ content was obtained.

¹H-NMR (500 MHz, CDCl₃): δ=7.99 (d, J=9.5 Hz, 1H), 6.41 (dd, J=2.0, 9.5Hz, 1H), 6.30 (d, J=2.5 Hz, 1H), 3.94-3.93 (m, 5H), 2.98 (td, J=2.0,12.5 Hz, 2H), 2.64-2.47 (m, 5H), 1.97 (d, J=12.5 Hz, 2H), 1.62 (qd,J=3.5, 12 Hz, 2H).

HRMS (ESI, [M+H]⁺) m/z: 342.2526.

Step 4: Preparation of2-methoxy-4-(4-(4-[D₃]methyl[3,3,5,5-D₄]piperazin-1-yl)piperidin-1-yl)aniline(the compound of Formula I-72)

As Step 4 in Example 3,2-methoxy-4-(4-(4-[D₃]methyl[3,3,5,5-D₄]piperazin-1-yl)piperidin-1-yl)aniline(0.85 g, 98.8% yield) with 93% of D₇ content was obtained.

¹H-NMR (500 MHz, CDCl₃): δ=6.63 (d, J=8.5 Hz, 1H), 6.53 (d, J=1.5 Hz,1H), 6.42 (dd, J=2.5, 8.0 Hz, 1H), 3.83 (s, 3H), 3.52 (d, J=12.5 Hz,2H), 2.64-2.59 (m, 7H), 1.93 (d, J=12.5 Hz, 2H), 1.72 (qd, J=3.5, 2H).

HRMS (ESI, [M+H]⁺) m/z: 312.2780.

Step 5: Preparation of(2-((5-chloro-2-((2-methoxy-4-(4-(4-[D₃]methyl[3,3,5,5-D₄]piperazin-1-yl))piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphorus oxide (the compound of Formula I-7)

As Step 4 in Example 1, (2-((5-chloro-2-((2-methoxy-4-(4-(4-[D₃] methyl[3,3,5,5-D₄]piperazin-1-yl))piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphorus oxide (0.28 g, 28.7% yield) with 93% of D₇ content wasobtained.

H-NMR (500 MHz, CDCl₃): δ=10.82 (s, 1H), 8.64 (dd, J=4.5, 8.5 Hz, 1H),8.11-8.10 (m, 2H), 7.51 (dd, J=7.5, 8.5 Hz, 1H), 7.32-7.27 (m, 2H), 7.14(td, J=2.0, 7.0 Hz, 1H), 6.56 (d, J=2.0 Hz, 1H), 6.50 (dd, J=2.0, 8.5Hz, 1H), 3.88 (s, 3H), 3.67 (d, J=12.0 Hz, 2H), 2.76-2.69 (m, 6H),2.47-2.44 (m, 1H), 1.99 (d, J=12.5 Hz, 2H), 1.86, 1.84 (2s, 6H), 1.75(qd, J=3.5, 12.5 Hz, 2H).

13C-NMR (125 MHz, CDCl₃): δ=157.77, 155.91, 154.94, 149.31, 147.41,143.92, 132.37, 129.56, 129.47, 123.06, 122.47, 122.37, 122.23, 120.56,119.82, 108.46, 106.07, 101.11, 61.86, 55.64, 50.49, 48.25, 28.16,18.88, 18.31.

HRMS (ESI, [M+H]⁺) m/z: 591.301.

EXAMPLE 9 Preparation of (2-((5-chloro-2-((2-methoxy-4-(4-(4-methyl[3,3,5,5-D₄]piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphorus oxide (the compound of Formula I-9)

Step 1: Preparation of 1-benzyl-4-[3,3,5,5-D₄]piperazine

In an ice bath, 1-phenyl[3,3,5,5-D₄]piperazine (15.0 g, 83.20 mmol) wasslowly added dropwise to a mixed solution of formic acid (15.6 g, 332.80mmol) and 37% formaldehyde solution (13.5 g, 166.40 mmol), and thenwarmed up to reflux. After the reaction was completed, the excess offormic acid in the reaction solution was removed by evaporation underreduced pressure. The residual liquid was adjusted with 10% NaOH aqueoussolution to be alkaline. Extraction with dichloromethane (75 mL×2) wasperformed and the organic phase was washed with saturated brine (50mL×2), dried over anhydrous sodium sulfate, filtered by suction andevaporated under reduced pressure to remove the solvent, to give a crudeproduct of 16 g. 1-benzyl-4-[3,3,5,5-D₄]piperazine (14 g, 87.5% yield)with 96% of D₄ content was obtained by column chromatography(dichloromethane:methanol=20:1).

HRMS (ESI, [M+H]⁺) m/z: 195.1789.

Step 2: Preparation of 1-methyl[3,3,5,5-D₄]piperazine

1-benzyl-4-[3,3,5,5-D₄]piperazine (11.2 g, 57.6 mmol) was dissolved inanhydrous methanol (45 mL), added with 10% Pd/C (2.2g) and heated to 50°C., allowing hydrogenation reaction to be performed. After the reactionwas completed, the reaction solution was cooled down to room temperatureand filtered by suction, and the filtrate was evaporated underatmospheric pressure to remove methanol, to give1-methyl[3,3,5,5-D₄]piperazine (5.8 g, 96.8% yield) with 96% of D₄content.

HRMS (ESI, [M+H]⁺) m/z: 105.1312.

Step 3: Preparation of1-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methyl[3,3,5,5-D₄]piperazine(the compound of Formula I-91)

1-(3-methoxy-4-nitrophenyl)piperidin-4-one (2.40 g, 9.59 mmol),1-methyl[3,3,5,5-D₄]piperazine (2.00 g, 19.20 mmol), acetonitrile (10mL), trimethyl orthoformate (2.00 g, 18.82 mmol) and formic acid (1.98g, 43.02 mmol) were respectively added in a 35 mL pressure tubing, andthe mixture was heated in a microwave to 110° C. and reacted for 90minutes. After the reaction was completed, the reaction solution wascooled down to room temperature, added with water (60 mL) and extractedwith ethyl acetate (50 mL×2). The aqueous layer was adjusted to analkaline pH by using 10% NaOH aqueous solution, extracted withdichloromethane (60 mL×2), washed with saturated brine (50 mL), driedover anhydrous sodium sulfate, and evaporated under reduced pressure toremove the solvent to give a crude product. After adding petroleum ether(10 mL), the crude product was beaten and filtered by suction to give1-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)-4-methyl[3,3,5,5-D₄]piperazine(1.42 g, 43.7% yield) with 96% of D₄ content.

¹H-NMR (500 MHz, CDCl₃): δ=7.99 (d, J=9.5 Hz, 1H), 6.42 (dd, J=2.5, 9.5Hz, 1H), 6.31 (d, J=2.5 Hz, 1H), 3.95-3.94 (m, 5H), 2.98 (td, J=2.5,12.5 Hz, 2H), 2.61-2.47 (m, 5H), 2.29 (s, 3H), 1.98 (d, J=12.5 HZ, 2H),1.63 (qd, J=3.5, 12.5 Hz, 2H).

HRMS (ESI, [M+H]⁺) m/z: 339.2344.

Step 4: Preparation of 2-methoxy-4-(4-(4-methyl [3,3,5,5-D₄]piperazin-1-yl)piperidin-1-yl)aniline (the compound of Formula I-92)

As Step 4 in Example 3,2-methoxy-4-(4-(4-methyl[3,3,5,5-D₄]piperazin-1-yl)piperidin-1-yl)aniline(1.1 g, 82% yield) with 96% of D₄ content was obtained.

¹H-NMR (500 MHz, CDCl₃): δ=6.65 (d, J=8.5 Hz, 1H), 6.54 (s, 1H), 6.43(d, J=7.0 Hz, 1H), 3.85 (s, 3H), 3.53 (d, J=12 Hz, 2H), 2.65-2.36 (m,7H), 2.31 (s, 3H), 1.94 (d, J=10.5 Hz, 2H), 1.74-1.1.72 (m, 2H).

HRMS (ESI, [M+H]⁺) m/z: 309.2628.

Step 5: Preparation of(2-((5-chloro-2-((2-methoxy-4-(4-(4-methyl[3,3,5,5-D₄]piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphorus oxide (the compound of Formula I-9)

As Step 4 in Example 1, (2-((5-chloro-2-((2-methoxy-4-(4-(4-methyl[3,3,5,5-D₄]piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphorus oxide (0.13 g, 35.13% yield) with 95.4% of D₄ content wasobtained.

¹H-NMR (500 MHz, CDCl₃): δ=10.79 (s, 1H), 8.63 (dd, J=4.5, 8.5 Hz, 1H),8.10-8.09 (m, 2H), 7.50 (dd, J=8.0, 8.0 Hz, 1H), 7.31-7.25 (m, 2H), 7.14(dd, J=1.0, 7.0 Hz, 1H), 6.56 (d, J=2.0 Hz, 1H), 6.50 (dd, J=2.0, 8.5Hz, 1H), 3.87 (s, 3H), 3.66 (d, J=12.0 Hz, 2H), 2.75-2.68 (m, 6H),2.48-2.43 (m, 1H), 2.40 (s, 3H), 1.98 (d, J=12.0 Hz, 2H), 1.85, 1.83(2s, 6H), 1.75 (qd, J=3.5, 12 Hz, 2H).

¹³C-NMR (125 MHz, CDCl₃): δ=157.77, 155.90, 154.94, 149.33, 147.42,143.85, 132.38, 129.56, 129.47, 123.12, 123.07, 122.50, 122.41, 122.21,120.60, 119.83, 108.46, 106.03, 101.12, 61.84, 55.65, 50.49, 48.27,45.46, 28.14, 18.85, 18.28.

HRMS (ESI, [M+H]⁺) m/z: 588.2936.

Effect Example 1 Evaluation of Stability of Liver Microsome In Vitro

300 μL of a final incubation system contains 30 μL of monkey livermicrosomes (protein concentration: 0.5 mg/mL, American BD Company), 30μL of NADPH+MgCl₂, 3 μL of a substrate (a solution of 1 μmol/L testcompound in acetonitrile) and 237 μL of PBS buffer solution. The aboveincubation system was made in duplicate, each of 0.3 mL.

For each sample, an evenly mixed solution of the substrate and enzymewith a total volume of 270 μL was first prepared, and afterpre-incubation at 37° C. for 5 min, 30 μL of NADPH +MgCl₂ was added andmixed. 40μL of the reaction solution was taken respectively at 0, 15,30, 60 and 90 min, and the reaction was stopped by 300 μL of ice-coldacetonitrile containing an internal standard. In addition, three blanks(KB) were set, each of 300 μL (KB1: no NADPH; KB2: no substrate; KB3: noenzyme).

40 μL of the incubation sample was pipetted out, added with 400 μL ofice-cold acetonitrile containing an internal standard, vortexed for 5min and centrifuged (13000 rpm, 4° C.) for 10 min. 80 μL of thesupernatant was pipetted out in a loading plate, and then 80 μL of 50%acetonitrile aqueous solution was added to the plate and mixed. 1μL ofthe mixture was pipetted out for LC/MS/MS assay and the chromatogram wasrecorded. The results of metabolic stability are shown in Table 1:

TABLE 1 metabolic stability in monkey liver microsomes Compounds t_(1/2)(min) Prolonging rates Brigatinib 170 — I-1 229 35% I-2 236 39% I-3 19917% I-4 176  4% I-6 223 31% I-7 227 34% I-9 214 26%

The compounds of the present invention (especially compounds I-1, I-2,I-6 and I-7) can significantly prolong the half-life period and havemore stable metabolism compared to the original drug Brigatinib.

Effect Example 2 Inhibition Effect on Proliferation In Vitro

1. Experimental Materials

1.1 Cells: human lung cancer cell line NCl—H3122, expressing EML4-ALKfusion protein.

1.2 Main reagents: sulfonyl rhodamine B, RPMI-1640 liquid medium,dimethyl sulfoxide (DMSO), trichloromethane (chloroform).

1.3 Instruments: Varioskan Flash microplate reader.

1.4 Solution preparation: an appropriate amount of a series of testcompounds was taken and dissolved using 5% chloroform+95% DMSO, to forma stock solution of 20 mM, which was stored at −20° C. in aliquots. Thepositive drug Crizotinib was taken and dissolved using 5% chloroform+95%DMSO, and the stock solution was diluted with fresh medium to a workingconcentration before use. 95 μl DMSO and 5 μl chloroform were taken,mixed together, and diluted with fresh medium to a working concentrationbefore use.

2. Test Methods:

2.1 Cell Culture and Inoculation

The tumor cell line used in tests was cultured in RPM11640 mediumcontaining 10% inactivated Hyclone serum or fetal bovine serum, 100IU/mL penicillin and 100 IU/mL streptomycin, in a 5% CO₂ incubator at37° C. NCl—H3122 cells were inoculated into a 96-well plate at5000/well. It was ensured that the cells were in logarithmic growthphase during the whole test.

2.2 Administration

Groups of series of test compounds, negative control and Crizotinib(positive control) were set up in this test. For each test compoundgroup, 6 concentration gradients by 3-fold serial dilution were set, andthree wells were for each concentration. For positive control group, 6concentration gradients by 3-fold serial dilution were set, and threewells were for each concentration. Negative control was 5% chloroform+95% DMSO (the same concentration as that of test compound at 100 nM),and 6 wells were set.

2.3 Sulfonyl rhodamine B method (SRB method)

After the cells were treated with the drugs for 72 hours, the culturemedium was discarded. A pre-chilled 10% trichloroacetic acid (TCA)solution was added into each well to fix the cells and the plate wasplaced in a refrigerator at 4° C. to fix. Each well of the plate waswashed with deionized water for 5 times to remove trichloroacetic acidsolution. After being dried in air, each well was added with SRBsolution (4 mg/ml) prepared with 1% acetic acid and then kept for 20minutes at room temperature. After the liquid was discarded, each wellwas washed with 1% acetic acid for 5 times to remove uncombined SRB dye,and then dried in air. An appropriate volume of 10 mM Tris-base(trimethylolamine methane) solution at pH 10.5 was added into each wellto dissolve the cells. The plate was shaken on a plate shaker for 10minutes. The absorbance (OD) value was measured at a wavelength of 490nm in a microplate reader.

2.4 Result processing

According to the OD values measured by microplate reader, an inhibitionrate was calculated as the following formula:

Survival rate (%)=OD of drug well/OD of control well×100% ,

If the survival rate was ≥100%, it was recorded as 100%.

Using Calcusyn software, IC₅₀ was calculated, and mean and standarddeviation thereof were calculated, and the data was expressed as:mean±standard deviation.

3. Test Results:

The results of inhibition effect on proliferation of human lung cancercell NCl—H3122 were shown in Table 2.

TABLE 2 Inhibition effect on proliferation of human lung cancer cellNCI-H3122 Compounds IC₅₀ (nM) Brigatinib 13.29 ± 1.60 I-1 10.02 ± 1.05I-2  9.45 ± 1.79 I-3 12.68 ± 2.37 I-4 11.11 ± 2.07 I-6  9.99 ± 2.31 I-7 9.89 ± 0.76 I-9  7.65 ± 1.07 Crizotinib 11.05 ± 0.69

The results in Table 2 show that the compounds of the presentapplication inhibit the proliferation of human lung cancer cellNCl—H3122 concentration-dependently, and have an excellent inhibitoryactivity.

1. A compound represented by Formula I, or a pharmaceutically acceptablesalt, solvate or prodrug thereof,

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium, provided that atleast one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ is selectedfrom deuterium.
 2. The compound, or the pharmaceutically acceptablesalt, solvate or prodrug thereof according to claim 1, wherein R₁ isselected from deuterium, and R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁are each independently selected from hydrogen or deuterium.
 3. Thecompound, or the pharmaceutically acceptable salt, solvate or prodrugthereof according to claim 2, wherein R₁ is selected from deuterium, R₄,R₅, R₆, R₇, R₉, R₁₀ and R₁₁ are selected from hydrogen and R₂, R₃ and R₈are each independently selected from hydrogen or deuterium.
 4. Thecompound, or the pharmaceutically acceptable salt, solvate or prodrugthereof according to claim 3, wherein R₁ is selected from deuterium, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen and R₂ and R₃are each independently selected from hydrogen or deuterium.
 5. Thecompound, or the pharmaceutically acceptable salt, solvate or prodrugthereof according to claim wherein R₂ and R₃ are selected fromdeuterium, and R₁, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are eachindependently selected from hydrogen or deuterium.
 6. The compound, orthe pharmaceutically acceptable salt, solvate or prodrug thereofaccording to claim 5, wherein R₂ and R₃ are selected from deuterium, R₆,R₇, R₈, R₉, R₁₀ and R₁₁ are selected from hydrogen, and R_(1,) R₄ and R₅are each independently selected from hydrogen or deuterium.
 7. Thecompound, or the pharmaceutically acceptable salt, solvate or prodrugthereof according to claim 5, wherein R₂ and R₃ are selected fromdeuterium, R_(1,) R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selected fromhydrogen, and R₄ and R₅ are each independently selected from hydrogen ordeuterium.
 8. The compound, or the pharmaceutically acceptable salt,solvate or prodrug thereof according to claim 5, wherein R₁, R₂ and R₃are selected from deuterium, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are selectedfrom hydrogen, and R₄ and R₅ are each independently selected fromhydrogen or deuterium.
 9. The compound, or the pharmaceuticallyacceptable salt, solvate or prodrug thereof according to claim 22,wherein R₄ and R₅ are selected from deuterium. R₆, R₇, R₈, R₉, R₁₀ andR₁₁ are selected from hydrogen, and R₁, R₂ and R₃ are each independentlyselected from hydrogen or deuterium.
 10. The compound, or thepharmaceutically acceptable salt, solvate or prodrug thereof accordingto claim 1, wherein R₆ and R₇ are selected from deuterium, and R₁, R₂,R₃, R₄, R₅, R₆, R₉, R₁₀ and R₁₁ are each independently selected fromhydrogen or deuterium.
 11. The compound, or the pharmaceuticallyacceptable salt, solvate or prodrug thereof according to claim 1,wherein R₈ is selected from deuterium, and R₁, R₂, R₃, R₄, R₅, R₆, R₇,R₉, R₁₀ and R₁₁ are each independently selected from hydrogen ordeuterium.
 12. The compound, or the pharmaceutically acceptable salt,solvate or prodrug thereof according to claim 11, wherein R₈ is selectedfrom deuterium, R₆, R₇, R₉, R₁₀ and R₁₁ are selected from hydrogen, andR₁, R₂, R₃, R₄ and R₅ are each independently selected from hydrogen ordeuterium.
 13. The compound, or the pharmaceutically acceptable salt,solvate or prodrug thereof according to claim 12, wherein R₈ is selectedfrom deuterium, R_(1,) R₆, R₇, R₉, R₁₀ and R₁₁ are selected fromhydrogen, and R₂, R₃, R₄ and R₅ are each independently selected fromhydrogen or deuterium.
 14. The compound, or the pharmaceuticallyacceptable salt, solvate or prodrug thereof according to claim 12,wherein, R₁ and R₈ is selected from deuterium, R₆, R₇, R₉, R₁₀ and R₁₁are selected from hydrogen, and R₂, R₃, R₄ and R₅ are each independentlyselected from hydrogen or deuterium.
 15. (canceled)
 16. The compound, orthe pharmaceutically acceptable salt, solvate or prodrug thereofaccording to claim 1, selected from the compounds of the followingformulas:


17. A pharmaceutical composition, comprising a therapeutically effectiveamount of the compound, or a pharmaceutically acceptable salt, solvateor prodrug thereof of any one of claim 1, and one or morepharmaceutically acceptable carriers or excipients.
 18. (canceled) 19.(canceled)
 20. A method of inhibiting anaplastic lymphoma kinase (AKL),comprising administering a therapeutically effective amount of acompound or a pharmaceutically acceptable salt, solvate or prodrugthereof of any one of claim 1, or a pharmaceutical composition of claim17 to patients in need thereof.
 21. (canceled)
 22. The compound, or thepharmaceutically acceptable salt, solvate or prodrug thereof accordingto claim 1, wherein R₄ and R₅ are selected from deuterium, and R₁, R₂,R₃, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are each independently selected fromhydrogen or deuterium.
 23. The compound, or the pharmaceuticallyacceptable salt, solvate or prodrug thereof according to claim 1,wherein R₂, R₃, R₄ and R₅ are selected from deuterium, and R_(1,) R₆,R₇, R₈, R₉, R₁₀ and R₁₁ are each independently selected from hydrogen ordeuterium.)
 24. The compound, or the pharmaceutically acceptable salt,solvate or prodrug thereof according to claim 1, selected from thecompounds of the following formulas: